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Full text of "Studies and synthetic applications of the O-stannyl ketyl-promoted cyclopropane fragmentations"

STUDIES AND SYNTHETIC APPLICATIONS OF THE 
O-STANNYL KETYL-PROMOTED CYCLOPROPANE FRAGMENTATIONS 



By 



ZHAOZHONG J. JIA 



A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL 
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT 
OF THE REQUIREMENTS FOR THE DEGREE OF 
DOCTOR OF PHILOSOPHY 



UNIVERSITY OF FLORIDA 
1996 



To the memory of my grandfather 



ACKNOWLEDGMENTS 



I owe thanks to many people in the chemistry department for the 
completion of this dissertation. First and foremost, I would like to thank my 
mentor and research director, Professor Eric Enholm, for all of his guidance, 
teaching, encouragement and support throughout graduate school. I greatly 
appreciate his hard efforts to help me grow into an organic chemist hand-by- 
hand. I appreciate his immeasurable help in the preparation of this manuscript. 

I thank the organic chemistry faculty, especially Professors Merle Battiste, 
William Dolbier and Tomas Hudlicky, for their enthusiasm and inspiring 
teaching to widen my knowledge and sharpen my thinking and understanding 
in organic chemistry. I thank Professor Jim Deyrup for offering me admission to 
such an outstanding chemistry department and for his kind help when I first 
arrived in this country alone and knew nobody. 

All the people in the Enholm group played a role in the completion of this 
dissertation and are acknowledged. Yongping Xie and Jeff Scheier worked 
patiently to improve my lab skills. Paul Whitley has been a good friend and 
constant source of fun and intellectual stimulation over the past four years. 
Kelley Moran, Jim Schulte II, Stan Toporek, Jennifer Lombardi and Maria 
Gallagher contributed to the stimulating and friendly environments of our lab 
and made lots of hard working hours more pleasurable. 

I thank Ion Ghiviriga and Fernando Gomez for their help on NOE and 2-D 
NMR studies. I thank Lucian Boldea, Patricia Bottari and Ivani Malvestiti, our lab 



iii 



neighbors, for their friendship and generosity in lending me their chemicals and 
glove box. 

My special thanks go to Xiaoxin Rong, my former roommate and one of 
my best friends here. He made me quickly adjusted to the American culture, 
assisted me to shop for my first car and trained me to drive, and always was 
there to help me through my difficult times. 

None of this would have been possible without my family's love. I thank 
my parents and grandparents for their enlightening guidance and endless 
encouragement and support to help me grow up and acquire more knowledge 
and better education. They and my uncles and aunts all supported me with their 
savings to generously sponsor my graduate school applications and my first trip 
to Florida from China. I thank my wife Yaping, for her enduring love, 
understanding and help during my graduate studies and the preparation of this 
dissertation. 

Finally I would like to acknowledge the National Science Foundation for 
its financial support to the work described in this dissertation. 



iv 



TABLE OF CONTENTS 

ACKNOWLEDGMENTS iii 

ABSTRACT vi 

CHAPTER 

1 INTRODUCTION 1 

2 STUDIES OF THE O-STANNYL KETYL-PROMOTED 
CYCLOPROPANE FRAGMENTATIONS 24 

3 APPLICATIONS OF THE O-STANNYL KETYL-PROMOTED 
CYCLOPROPANE FRAGMENTATIONS TO THE SYNTHESIS 

OF TRIQUINANE COMPOUNDS 53 

4 OTHER INVESTIGATIONS OF THE O-STANNYL KETYL- 
PROMOTED CYCLOPROPANE FRAGMENTATIONS 68 

Application of the Post-Fragmentation Tin(IV) Enolates 68 

Cyclopropane Fragmentation-Allylation by Allyltributyltin 72 

5 SUMMARY 78 

6 EXPERIMENTAL 80 

General Methods 80 

Experimental Procedures and Results 81 

LIST OF REFERENCES 1 1 4 

BIOGRAPHICAL SKETCH 1 21 



v 



Abstract of Dissertation Presented to the Graduate School 
of the University of Florida in Partial Fulfillment of the 
Requirements for the Degree of Doctor of Philosophy 

STUDIES AND SYNTHETIC APPLICATIONS OF THE 
O-STANNYL KETYL-PROMOTED CYCLOPROPANE FRAGMENTATIONS 

By 

Zhaozhong J. Jia 
December, 1996 

Chairman: Eric J. Enholm 
Major Department: Chemistry 

This dissertation investigated the O-stannyl ketyl-promoted cyclopropane 
fragmentations. O-stannyl ketyls were generated by the reactions of cyclopropyl 
ketones with tributyltin hydride or allyltributyltin. The goal of this study was to 
examine the reactivities of these cyclopropanes and examine the mechanistic 
attributes governing the cyclopropane fragmentation process, such as 
stereoelectronic effects and radical-stability effects. Another goal of this study 
was to apply the O-stannyl ketyl-promoted cyclopropane fragmentations to 
organic synthesis. 

The first area of study was the O-stannyl ketyl-promoted cyclopropane 
fragmentations using tributyltin hydride. A variety of cyclopropyl ketone 
precursors were examined, including tricyclo[3.3.0.0 2 - 8 ]octan-3-one substrates. 
These fragmentations were governed by both stereoelectronic effects and 
radical-stability effects. 



vi 



The second area of study was the synthetic applications of the O-stannyl 
ketyl-promoted cyclopropane fragmentations. The O-stannyl ketyl-promoted 
cyclopropane fragmentation-cyclization tandem sequence was accomplished. 
The efficient synthesis of two triquinane molecules demonstrated this tandem 
sequence and a novel synthetic methodology for triquinane compounds. 

The third area of study included the preliminary work on the tin(IV) 
enolates generated in the cyclopropane fragmentations. Their applications in 
aldol and alkylation reactions were successful. Allyltributyltin-induced 
cyclopropane fragmentation-allylation reactions were also preliminarily 
examined. 



vii 



CHAPTER 1 
INTRODUCTION 



The term "free radical" applies to a species possessing one unpaired 
electron. 1 A free radical is generated by homolytic cleavage of a covalent bond. 
The central atom is usually sp 2 hybridized and the unpaired electron resides in 
the p-orbital. 2 Though free radicals are highly reactive intermediates, reactions 
involving them generally embrace mild reaction conditions, in contrast to the 
harsh reaction conditions associated with the generation of cations or anions. 

Free radical chemistry dates back to 1900 when Gomberg investigated 
the formation and reactions of triphenylmethyl radical. 3 However, free radicals 
had little synthetic use until the 1970s. 4 In that decade, new synthetic methods 
involving free radicals began to be developed. The understanding and synthetic 
applications of radicals have grown quickly since. Today free radical reactions 
have been a routine method to accomplish constructions of a wide variety of 
carbon and hetereoatom skeletons. 5 

Organotin compounds have been extensively studied for decades. 6 
Among them, tributyltin hydride (TBTH) has been known for over 30 years to 
engage in free radical reactions. It is commercially available and can be readily 
prepared as well. 6 - 7 Tin has a 5s 2 5p 2 electronic configuration and exists in 
tetrahedral sp 3 hybridization in TBTH. The Sn-H bond in TBTH is of 0.17 nm in 
length and 73.7 kcal/mol in bond dissociation energy (BDE). 6d .9-8 This bond 
can be homolytically-cleaved with a radical initiator to produce a tributyltin 



1 



2 



radical. Azo and peroxide compounds are common free radical initiators, 
possessing a weak C-N bond or 0-0 bond, as shown in Figure 1-1. 2a 



Name 



Structure 



Temperature for 
BDE (kcal/mol) 1-hr Half-life (°C) 



AIBN NC- 



■N=N 



CN 30 



O 



O 



acetyl 

peroxide Me — "—0-0— "—Me 

■ 
benzoyl 

peroxide Ph— "— 0-0— Ph 



30-32 



30 



85 



85 



95 



f-butyl 
peroxide 



■0-0- 



37 



150 



Figure 1-1 
Common free radical initiators 



The combination of TBTH 1 and initiator AIBN (azobisisobutylnitrile) 2 in 
refluxing benzene (80°C) is the most popular way to generate tributyltin radical. 
As shown in Scheme 1-1, thermal decomposition of AIBN produces 
cyanoisopropyl radical 3, which abstracts a hydrogen atom from the Sn-H bond 



NC- 



N=N- 
2 



CN 



Y + H- 
CN 

3 1 



SnBu 3 



I + N 2 
CN 

3 



H 



CN 
4 



+ 'SnBua 
5 



Scheme 1-1 



3 



of TBTH to give tributyltin radical 5. 

There are five broad classes of free radical reactions, 9 as shown in 
Scheme 1-2: i) radical combination (coupling) (eq. 1); ii) radical abstraction of 
an atom or group (eq. 2); iii) radical addition to a multiple bond (eq. 3); iv) 
radical fragmentation (p-elimination), the reverse process of addition (eq. 4); v) 
radical rearrangement (eq. 5). 





. . A 
+ r\ 






R* 


+ A-B 


► R-A + «B 


(eq. 2) 


R. 


+ A = B 


► R-A-B- 


(eq. 3) 


R- 


A-B- 


► R« + A = B 


(eq. 4) 


R- 


A-B. 


'A-B-R 


(eq. 5) 






Scheme 1-2 






Bu 3 Sn» + 


R-X ► Bu 3 Sn-X 


+ R. 




5 


6 7 


8 




R- + 


Bu 3 SnH ► R-H + 


Bu 3 Sn« 




8 


1 9 


5 



Scheme 1-3 

The atom or group abstraction reactions (eq. 2) of tributyltin radicals are 
very useful. Halide abstraction is of great synthetic importance. 6 9 Bromide and 
iodide are most commonly used. As shown in Scheme 1-3, halide reduction 
occurs through a chain mechanism. Tributyltin radical 5 abstracts halogen atom 
X from halide 6, generating carbon-centered radical 8. Radical 8 abstracts a 
hydrogen atom from TBTH, giving reduction product 9 and another tributyltin 



4 



radical to carry on this chain reaction. Depending on its structure, radical 
intermediate 8 may undergo addition, fragmentation or rearrangement 
reactions before the final hydrogen abstraction occurs. 

TBTH reduces thiols, thioethers and selenides as well, due to the 
formation of strong Sn-S or Sn-Se bonds. 6 9 Barton developed this reduction 
into a powerful deoxygenation method, 10 which can be applied to a wide 
variety of hydroxy compounds, including primary, secondary, tertiary alcohols 
and diols. The general sequence of a Barton deoxygenation is shown in 
Scheme 1-4. This reaction proceeds through an addition of tributyltin radical to 
the thiocarbonyl group, followed by fragmentation of carbon-centered radical 
12 to liberate alkyl radical 8 and restore the carbonyl function. Radical 8 
abstracts a hydrogen atom from TBTH, giving reduction product 9. The Y group 
can be hydrogen, methyl, phenyl, S-methyl, S-phenyl, O-phenyl and 
imidazolyl.69 

s ,SnBu 3 

R-OH—^A !^R s X 

O Y 

10 11 12 

,SnBu 3 

S 

TBTH 

► Jv + R« ► R-H 

O \ -Bu 3 Sn« 

13 8 9 

Scheme 1-4 

The addition of a free radical to a multiple bond constructs a new o-bond 
at the cost of a rc-bond, as shown by eq. 3 in Scheme 1-2. Though this addition 
is energetically favorable, it is still considered reversible. The rate of this radical 
addition is influenced by the stabilities of R», multiple bond A=B, and radical 



5 



RAB« formed by the addition; steric hindrance to the addition step; and polar 
factors. 23 The substituents on R» and on the multiple bond play important roles 
in this addition. These substituent effects can be understood through the frontier 
molecular orbital (FMO) theory. 1 1 > 1 2 

In the FMO theory, patterns of reactivity can often be addressed in terms 
of interactions between the FMOs in the two reacting species. The FMO of a free 
radical is its "singly occupied" molecular orbital (SOMO). The FMOs of a 
multiple bond are its "highest occupied" molecular orbital (HOMO) and "lowest 
unoccupied" molecular orbital (LUMO). 1 2 A very important determinant of the 
activation energy of this reaction is the SOMO-HOMO and SOMO-LUMO 
interactions. Since orbital interaction is stronger for orbitals of comparable 
energy, one of these two interactions is usually more significant than the other if 
the SOMO-HOMO energy gap and the SOMO-LUMO energy gap are not equal. 
Any substituent on either the radical or the multiple bond lowering the SOMO- 
HOMO or SOMO-LUMO energy gap lowers the activation energy of this 
addition. 11.1 2 

The electronic characteristics of radicals and multiple bonds are defined 
as the following. An "electrophilic" radical, possessing an electron-withdrawing- 
group (EWG) substituent, has an energy-lower SOMO. A "nucleophilic" radical, 
possessing an electron-donating-group (EDG) substituent, has an energy- 
higher SOMO. An "electron-rich" multiple bond, possessing an EDG, has an 
energy-higher HOMO. An "electron-deficient" multiple bond, possessing an 
EWG, has an energy-lower LUMO. 1 2 

A favorable SOMO-HOMO or SOMO-LUMO interaction is required for a 
radical addition reaction to occur, as shown in Figure 1-2. For an electrophilic 
radical (low SOMO), its interaction with the HOMO is usually more significant 
than that with the LUMO. For a nucleophilic radical (high SOMO), the SOMO- 



6 



LUMO interaction is usually stronger than the SOMO-HOMO interaction. 11 Alkyl 
radical is nucleophilic, and its interaction with a receiving multiple bond is thus 
mainly in a SOMO-LUMO manner. 



somo-^;' 



,4, 



A=B 



LUMO 



A=E 



SOMO 



' A=B 



LUMO 



HOMO 



4 



SOMO-HOMO interaction 



HOMO 
A=B 

SOMO-LUMO interaction 



Figure 1-2 

Orbital interactions of a radical with a multiple bond (eq. 3) 



AIBN^ Bu 3 Sn ^ 
•SnBu 3 -^f R_X 



-X 6 




Formation of carbon-carbon bonds is the heart of organic synthesis. With 
a new carbon-carbon bond constructed, the addition of an alkyl radical to an 
alkene or alkyne is synthetically important. 1 For this radical intermolecular 
addition to be successful, a selectivity requirement must be fulfilled. This 
requirement pertains to intermediates 5,8, and 15 (Scheme 1-5). 1 Each 



7 



intermediate should have a specific partner to react with. If 8 and 15 have the 
same tendency to add to alkene 14, polymerization can result. To prevent 
polymerization, the electronic characteristics of 8 and 15 must be opposite in 
nature so that they have different reactivities towards alkene 14. 

To fulfill the selectivity requirement, a combination of nucleophilic alkyl 
radical 8 and electron-deficient alkene 14 (Y=EWG) is popular. 13 Nucleophilic 
8 readily reacts with 14, producing electrophilic 15. This radical does not react 
with electron-deficient 14 and will eventually be quenched by TBTH to give 16. 
The reaction of eq. 5 (Scheme 1-6) is such an example. Alkene 18 is electron- 
deficient, due to the cyano group. Under TBTH treatment iodide 17 provides 
nucleophilic cyclohexyl radical. However, the combination of electrophilic 8 and 
electron-rich 14 (Y=EDG) works well too. As shown in eq. 6, 21 is electron-rich, 
and electrophilic radical is generated from chloride 20. 




20 21 22 



Scheme 1-6 

After a new carbon-carbon bond forms in an addition, adduct radical 26 
can be transformed into a non-radical product not only by a hydrogen 
abstraction from TBTH, but also by homolytically cleaving a p-bond to split off 
radical 26, as shown in Scheme 1-7. 1 This fragmentation prevents radical 24 



8 

from reacting with alkene 23. If this p-elimination is fast enough, radicals 8 and 
24 need not to be of different electronic characteristics. 

r- + A/ Y — - R \/\y Y — - R \/\ + y. 

8 23 24 25 26 

Scheme 1-7 

Keek's allylation reactions involve such a p-elimination. 14 Keck used 
allyltributyltin 27 to intermolecularly accept alkyl radical 8, as shown in Scheme 
1-8. Once adduct 28 forms, the C-Sn bond p to the radical center rapidly 
fragments, giving tributyltin radical 5 and allylated product 25. Radical 5 then 
abstracts the X group from 6, reproducing alkyl radical 8 to renew the reaction 
cycle. Substrate 6 can be a halide, thioether, selenide or xanthate. A variety of 
substrates 6, including carbohydrate derivatives, can be applied (Scheme 1- 
9).14 




Scheme 1-8 



9 



) V AIBN ) V 



29 (X=CI, SPh) 
OH 



80-90% 



HO,, # Js-OBz /V " " 3 HO„. 
ecAo^ 6 ' 



hv 

91% 



MeO ' 




31 



32 



Scheme 1-9 



"Cyclizations" are intramolecular additions. A typical 5-hexenyl radical 
cyclization is shown in Scheme 1-10. 1 The cyclization rate constant of 5- 
hexenyl radical 34 to cyclopentylmethyl radical 35 is about 10 5 s -1 at 25°C. It 



1 Bu 3 SnH 




1 Bu 3 SnH 



Scheme 1-10 



10 



can be further increased by making the alkene electron-deficient with an EWG 
substituent. 15 Although radicals 34 and 35 have the same nucleophilicity, the 
selectivity requirement for chain reactions can still be fulfilled: 34 cyclizes to the 
alkene, whereas 35 only reacts with TBTH in an intermolecular manner. 

Free radical cyclizations are powerful methods for five- and six- 
membered ring constructions. Molecular geometry is a key factor to influence 
the regioselectivity and stereochemistry of the cyclizations. The cyclizations of 
5-hexenyl radical 34 have been extensively studied and proceed in a highly 
regioselective manner. 16 ' 17 In almost all cases, 5-hexenyl radicals 
preferentially engage in 5-exo cyclizations, following Baldwin's rule. 18 The 5- 
exo cyclization product 35 forms faster than the 6-endo product 37 in a ratio of 
50:1 , as shown in Scheme 1 -1 1 . 1 6 




(50:1) 



+ 




34 



35 



37 



Scheme 1-11 




n + 
+ 



Figure 1-3 

Beckwith's chair transition state for 5-hexenyl radical cyclization 



According to Beckwith, 5-hexenyl radical cyclization proceeds through a 
chair-like transition state (Figure 1-3), with substituents preferring pseudo- 



11 



equatorial positions on the six-membered ring. 16 The stereochemistry of the 
major cyclization product is determined by this chair-like transition state, as 
demonstrated by the examples in Scheme 1-12. 1 




"Fragmentation" is the reverse process of an addition. The B-elimination 
of tributyltin radical in Keek's allylation (Scheme 1-8) is a radical fragmentation. 
A new radical and a new multiple bond are generated in the homolytic cleavage 
of a c-bond. The cleavage of an adjacent strained ring, such as a cyclopropane, 
cyclobutane or epoxide, is a special type of radical fragmentation, as shown in 
Scheme 1-13. The strain energy in a simple cyclopropane is 28.3 kcal/mol, 
while that in a simple cyclobutane is 27.4 kcal/mol and that in a simple epoxide 
is 27.2 kcal/mol. 19 Though these free radical ring cleavage and closure 
processes are considered reversible, the ring cleavage occurs at a much higher 
rate to release ring strains. 1 . 1 5a,b For example, the rate constant for ring 
opening of cyclopropylcarbinyl radical 46 (Y=CH2) to allylcarbinyl radical 47 



12 



(Y=CH2) is 1.3 x 10 s s _1 at 25°C, while the rate constant for the reverse process 
is only 4.9 x 10 3 s _1 . 15a 

— Cj — - ^/ Y- 

46 47 

= ^^Y- 

48 49 

Scheme 1-13 

A simple strained-ring fragmentation is of limited synthetic importance. 
However, when this fragmentation couples with another free radical reaction, a 
variety of tandem sequences can result. 20 




Dowd demonstrated an interesting "cyclization-fragmentation" tandem 
sequence, as shown in Scheme 1-14 . 21 In this process, radical 51 first adds to 



13 



the carbonyl, giving cyclopropane 52. Due to the ring strain, this cyclopropane 
is unstable and fragments to afford ester-stabilized radical 53, which abstracts a 
hydrogen from TBTH to give 54 and a tributyltin radical to renew the reaction 
cycle. This sequence expands cyclohexanone 50 to cycloheptanone 54. 

A free radical "fragmentation-cyclization" sequence was accomplished by 
Motherwell, as shown in Scheme 1-1 5. 22 Radical 56 cleaves the adjacent 
cyclopropane, giving radical 57 which cyclizes onto an alkyne ether to construct 
a spiro ring skeleton. Vinyl radical 58 reacts with TBTH to abstract a hydrogen 
atom in the final step. 



S 




Scheme 1-15 



Boger realized a radical "cyclization-fragmentation-cyclization" tandem 
sequence, as shown in Scheme 1-16.23 Unstable cyclopropane intermediate 
62 first forms through a radical cyclization onto the carbonyl. The cyclopropane 
fragments to produce tertiary radical 63 which is captured by an alkyne tether in 
the following 5-exo-dig cyclization. 



14 




Scheme 1-17 

Free radical-induced epoxide fragmentation offers a convenient method 
to generate reactive oxygen-centered radicals. 1 This epoxide fragmentation 
also can be used in synthetically useful tandem sequences, as demonstrated in 
Scheme 1-17. 24 A radical is generated a to epoxide in 67. The epoxide's C-0 



15 



bond selectively cleaves, giving oxygen-centered radical 68. Through a 1,5- 
hydrogen migration, radical 68 intramolecularly abstracts a hydrogen atom, 
affording carbon-centered radical 69. Radical 69 cyclizes onto the olefin to 
produce bicycle 70. 

TBTH reduces aldehydes and ketones to alcohols. 6 9 Depending on 
reaction conditions, two different mechanisms are postulated for the initial 
hydrostannation step of the reduction, as shown in Scheme 1-18. 6 9 When polar 
solvent and Lewis acid catalyst are used, the ionic pathway dominates (eq. 7). 
In this mechanism, TBTH acts as a hydride donor, giving intermediate 73 which 
reorganizes to afford tin alkoxide 74. The tin moiety is subsequently released 
by hydrolysis with water, alcohols or acids, yielding alcohol. 



SnBuc 



72 



Lewis 
Acid 



Polar 
Solvent 



Bu 3 Sn 



73 



O 



H 



OSnBu 3 



H 



74 



(eq. 7) 



^X^+ H-Sn 



OSnBuo OSnBuo 

Bu 3 JHH I (eq . 8) 

' ^ - BuoSn* 



72 



PhH 



Bu 3 Sn- 



H 



75 

Scheme 1-18 



74 



A free radical pathway is postulated when the combination of TBTH and 
AIBN in benzene is used (eq. 8). 6 9 O-stannyl ketyl radical 75 initially forms 
through the addition of oxophilic tributyltin radical to carbonyl 72. This carbon- 
centered ketyl radical 75 abstracts a hydrogen from TBTH, producing tin 
alkoxide 74 and regenerating tributyltin radical to renew the reduction process. 
Alcohol product is obtained by hydrolysis of 74. 



16 



The chemistry of O-stannyl ketyls is the focus of this dissertation. An 0- 
stannyl ketyl can be viewed as a pseudo-protected radical anion, because the 
O-Sn bond has a certain degree of ionic character, due to the electronegativity 
difference between oxygen and tin (Scheme 1-19). The early investigations of 
this chemistry in the 1970s were mainly concentrated on mechanistic studies of 
the O-stannyl ketyl-promoted fragmentations of simple cyclopropyl ketones and 
a,(3-epoxyketones. 6 9.25 it was not until the mid-1980s when chemists finally 
began to examine O-stannyl ketyls for a synthetic purpose. 

5+ + 
^SnBuo 8- .SnBuo - SnBuo 

O O O 

75 76 77 

Scheme 1-19 

The year 1985 welcomed the earliest synthetic work on O-stannyl ketyls. 
Tanner performed a series of investigations to study ketone reduction by 
organotin hydrides. 26 O-stannyl ketyl-promoted cyclopropane fragmentations 
were once again examined using cyclopropyl phenyl ketone. Rahm studied the 
effect of high pressure on ketone reduction by TBTH, including cyclopropyl 
ketones and a,p-epoxyketones. 27 

In 1986, Beckwith accomplished the cyclization of O-stannyl ketyl onto a 
multiple bond, as shown in Scheme 1-20. 28 Though the yield was excellent, 
this reaction was sluggish and required excess TBTH. It took 40 hours for the 
cyclization to complete. Similar O-stannyl ketyl cyclizations were reported by 
Julia (1987) and by Ueda (1988). 29 .30 



17 




Scheme 1-20 

Enholm has been actively engaged in the synthetic studies of O-stannyl 
ketyls since 1989. 31 "37 He envisioned that the cyclization of nucleophilic O- 
stannyl ketyl would be much faciliated if the ketyl-accepting multiple bond was 
electron-deficient. 31 Enholm demonstrated that aldehydes and ketones could 
readily cyclize onto tethered olefinic appendages under treatment of TBTH and 




O 




86 87 



Scheme 1-21 



18 



AIBN, as shown in Scheme 1-21. 31 Both 5-exo and 6-exo cyclizations of olefins 
"activated" by an EWG substituent, such as an ester, nitrile or phenyl, were 
achieved. 




Scheme 1-22 

Enholm realized O-stannyl ketyl-promoted tandem radical cyclizations. 32 
He synthesized spiro (eq. 9) and fused (eq. 10) bicycles, as shown in Scheme 
1-22. Activated olefin engaged in the first cyclization. Nucleophilic O-stannyl 



19 



ketyl radical cyclized onto this electron-deficient olefin, affording electrophilic 
radical (92 and 95) which cyclized onto the electron-rich olefin tether. 



O OSnBu 3 OSnBu 3 OSnBu 3 

TBTH R/"^ __R^^ TBTH^r 1 ^S 1 




99 100 

Scheme 1-23 



Enholm examined allylic O-stannyl ketyls 99, produced by the reaction of 
a,p-unsaturated carbonyls with TBTH, as shown in Scheme 1-23. 33 - 34 Allylic 
ketyl radical 99, once generated, enjoys resonance with the adjacent olefin 
moiety to give 100, a combination of tin(IV) enolate and free radical. Enholm 
demonstrated that this free radical could be intramolecularly captured by an 
olefin tether, as shown in Scheme 1-24. 33 



85% 



C0 2 Me 

' O 




102 



OSnBu 3 
103 



C0 2 Me 




C0 2 Me 



OSnBu 3 
104 



tbjh^ y-sj 

-Bu 3 Sn. T 

/ ^OSnBu 3 
105 




C0 2 Me X 0H 




106 

Scheme 1-24 



O 

107 



20 



Enholm discovered that for allylic O-stannyl ketyls, after free radical 100 
was quenched by a hydrogen abstraction from TBTH, tin(IV) enolate 101 could 
undergo a variety of interesting reactions, including intramolecular (eq. 11) and 
intermolecular (eq. 12) aldol condensation and alkylation reactions (eq. 13), as 
shown in Scheme 1-25. 34 These observations are in direct contrast to how an 
a,|3-unsaturated ketone is normally viewed in free radical reactions, where it 
often functions as electron-deficient radical acceptor in a 1 ,4-addition manner. 




111 112 113 




(eq. 13) 



114 115 116 

Scheme 1-25 

O-stannyl ketyls are suitable for cyclizations with hetereoatom-substituted 
carbon-carbon double bonds or carbon-nitrogen double bonds, demonstrated 
first by Ueda in 1988.30 Kim observed O-stannyl ketyl cyclization onto imine. 38 
Shibuya achieved cyclization with oxazolidinone as the ketyl acceptor (eq. 14, 
Scheme 1-26). 39 Naito reported cyclization of O-stannyl ketyl with oxime ether 



21 



119 (eq. 15). 40 Lee found that (3-alkoxyacrylate 121 was an efficient ketyl 
acceptor, and accomplished the synthesis of fused oxacycle 123 (eq. 16). 41 




121 122 123 



Scheme 1-26 

The 1990s witnessed the reinvestigation of O-stannyl ketyl-induced 
epoxide fragmentations. Hasegawa reported the selective C-0 bond cleavage 
of a.p-epoxy ketones by thermal and photochemical reactions with TBTH. 42 
Bowman studied the epoxide fragmentation in 2-ketobicyclo[2.2.1]heptan-3- 
spiro-2'-oxirane substrates and reached the same conclusion. 4 3 Rawal and 
Kim accomplished an interesting tandem sequence using this fragmentation, as 
shown in Scheme 1-27 44 Similar to that in Scheme 1-19, this sequence 
started from selective cleavage of the epoxide's C-0 bond, giving reactive 
oxygen-centered radical 126, which promoted a 1,5-hydrogen abstraction and 



22 



a radical cyclization. Tributyltin radical was ejected from rearranged O-stannyl 
ketyl 128 to restore the original carbonyl function. 




OH OH OH 

127 128 129 

Scheme 1-27 



Free radicals have been among the most extensively used intermediates 
in organic synthesis. 5 Unfortunately, O-stannyl ketyl is much less studied and 
still poorly understood. As pointed out before, although the O-stannyl ketyl- 
promoted cyclopropane fragmentation has been known for over 25 years, 25 
this reaction was only examined using simple molecules for mechanistic 
interests. No synthetic application of this fragmentation had ever been reported 
prior to the work described in this dissertation. In order to continue the 
exploration and understanding of O-stannyl ketyls, this dissertation investigates 
the O-stannyl ketyl-promoted cyclopropane fragmentations with a wide variety 
of substrates. This dissertation demonstrates a novel O-stannyl ketyl-initiated 
cyclopropane fragmentation-cyclization tandem sequence and applies it to the 
efficient synthesis of two triquinane molecules. This dissertation also examines 
the chemistry of tin(IV) enolates, produced in cyclopropane fragmentations. 



23 



Chapter 2 describes the studies of O-stannyl ketyl-promoted 
cyclopropane fragmentations using simple, bicyclic and tricyclic substrates. A 
special tricyclic substrate, tricyclo[3.3.0.o2.8]octan-3-one, was treated with 
TBTH to produce different ring cleavage products, depending on the location 
and type of substituent present. An examination of both radical-stabilizing 
substituents and stereoelectronic effects was carried out to understand which 
factors biased the bond cleavage in a rigid a-ketocyclopropane. 

Chapter 3 examines the tandem sequence arising from O-stannyl ketyl- 
promoted cyclopropane fragmentation and following radical cyclization. This 
radical tandem sequence gave high yields in good stereoselectivity. This work 
accomplished the novel synthesis of an angular and a linear triquinane model 
compound. This is the first ever known example of the O-stannyl ketyl-initiated 
cyclopropane fragmentation-cyclization tandem reactions. 

Chapter 4 demonstrates the applications of tin(IV) enolates generated in 
cyclopropane fragmentations. These tin(IV) enolates could engage in aldol 
condensation and alkylation reactions. Chapter 4 also examines the 
allyltributyltin-induced cyclopropyl ketone fragmentation-allylation. 

The viability of free radicals as powerful synthetic intermediates has been 
well proved. 5 Free radicals are generated under mild and neutral conditions, 
tolerate a wide range of functionalities, and usually react regioselectively and 
stereoselective^. O-stannyl ketyl radicals possess unique attributes in organic 
synthesis. The work described in this dissertation broadens the knowledge of 
this special ketyl species. O-stannyl ketyl-promoted cyclopropane fragmen- 
tation produces a free radical along with a regiospecific tin(IV) enolate. This 
work individually manipulates these two intermediates. Further efforts to take 
advantage of them both will definitely lead to exciting developments. 



CHAPTER 2 

STUDIES OF THE O-STANNYL KETYL-PROMOTED 
CYCLOPROPANE FRAGMENTATIONS 



The origin of this work was the mechanistic studies of the O-stannyl ketyl- 
promoted cyclopropane fragmentations in the early 1970s by Godet and 
Pereyre. 2 5a,b,c They found that under free radical conditions, the reaction of 
cyclopropyl ketone 130 with TBTH gave cyclopropane scission product 134, as 
shown in Scheme 2-1. In this reaction, the carbonyl was first reduced to O- 
stannyl ketyl 131, which cleaved the adjacent cyclopropane. Radical product 

132 was reduced by hydrogen abstraction from TBTH, giving tin(IV) enolate 

133 and reproducing tributyltin radical to carry on the chain process. Enolate 
133 was finally hydrolyzed to 134. This fragmentation mechanism was 
confirmed later by other independent studies.25-27 



OSnBu 3 OSnBu 3 

*\J - Bu 3 Sn. 

131 132 




O-stannyl ketyl-promoted cyclopropane fragmentations are synthetically 
valuable. At the expense of a cyclopropyl ketone, an alkyl radical and a tin(IV) 



24 



25 



enolate are produced. Although the original investigators did not explore either, 
both the radical and tin(IV) enolate are useful intermediates in organic 
synthesis. Cyclopropyl ketone 130 can be readily prepared by a variety of 
methods, such as using an a,|3-unsaturated ketone and sulfur ylide, 4 ^ or 
cyclopropanating an allylic alcohol and then oxidizing the product, 46 or 
cyclopropanating an alkene with a diazo function and a transition metal catalyst 
intramolecularly or intermolecularly. 47 

The synthetic applications of the O-stannyl ketyl-promoted cyclopropane 
fragmentations had not been known prior to the work described in this 
dissertation. Inspired by Motherwell's free radical cyclopropane fragmentation- 
cyclization tandem sequence (Scheme 1-15), 22 we planned to examine this 
sequence promoted by O-stannyl ketyl. 




137 138 

Figure 2-1 

The simple cyclopropyl ketones for the fragmentation studies 



To initiate our investigation of the O-stannyl ketyl-promoted cyclopropane 
fragmentations, four simple cyclopropyl ketones, shown in Figure 2-1, were 
planned. The preparation of substrates 135 and 136 was first planned as that 
shown in Scheme 2-2, starting from commercial aldehydes 139 and 140. 
Addition of vinyl Grignard to the aldehydes gave allylic alcohols 141 and 142 



26 



in quantitative yields. Swern reaction was used to oxidize the alcohols to vinyl 
ketones 143 (52%) and 144 (52%). 48 Sulfur ylide method was employed to 
produce cyclopropyl ketones 135 (18%) and 136 (24%) in modest yields. 45 

O v MrBr H _ 

i Swern oxidation 



X 



FT^H thf r 
139R=C 9 H 19 100%141 R= C 9 H 19 

140R= C 5 H 11 100% 142 R= C 5 H 11 s ^\y 

O — S = l U o 

! R ^1 

R NaH, DMSO R ^sl 

52%143R= C 9 H 19 18% 135 R= C 9 H 19 

52%144 R= C 5 H 11 [y\y 24% 136 R= C 5 H 11 \J\S 

Scheme 2-2 



OH ^s^OCOsMe 



R ^ RuH 2 (PPh 3 ) 4 
141R=C 9 H 19 PhMe.A 83% 143 R= C 9 H 19 
142 R= C5Hl1 v y\/ 69%144 R= C 5 H 11^^/ 



/wwV 



OH 

Mn0 2 

no reaction 



CH 2 CI 2 or CHCI 3 , reflux 

141 

Scheme 2-3 



27 

To improve the yields, a ruthenium-catalyzed oxidation method with ally I 
methyl carbonate was used, 49 affording vinyl ketones 143 (83%) and 144 
(69%), as shown in Scheme 2-3. Mn02 oxidation was attempted as well. 50 
However, no oxidation was observed, even when the reaction mixture in 
chloroform was refluxed. 

The preparation of cyclopropyl ketones 135 and 136 was also achieved 
by an alternative route shown in Scheme 2-4. The Grignard reagent of 
cyclopropyl bromide reacted with aldehydes 139 and 140, providing 
cyclopropyl alcohols 145 (76%) and 146 (70%). Pyridinium chlorochromate 
(PCC) oxidized them to desired substrates 135 (83%) and 136 (78%). 



[^MgBr ^ OH 

R' "H THF R^<] 



A. 



139 R= C 9 H 19 76% 145 R= C 9 H 19 

140R= C 5 H 11 70% 146 R= C 5 H 11 



PCC 
► 

CH2CI2 

83% 135 R= C 9 H 19 

78% 136 R= C 5 H 11 \J\y 

Scheme 2-4 



Cyclopropyl ketone 137 was commercially available. The preparation of 
substrate 138 was accomplished in quantitative yield from frans-chalcone 147 
with sulfur ylide, 45 as shown in Scheme 2-5. 

The O-stannyl ketyl-promoted cyclopropane fragmentations of these 
simple substrates occurred readily in refluxing benzene, giving cyclopropane- 
scission products in good yields, as shown in Scheme 2-6. 



28 




147 



135 



O 






NaH, DMSO 
1 00% 

Scheme 2-5 
TBTH, AIBN 

9 

PhH, reflux 
80% 



TBTH, AIBN 
► 

PhH, reflux 
80% 

TBTH, AIBN 
► 

PhH, reflux 
92% 



138 




148 

y 

149 



H /^X TBTH, AIBN / \ 

" H \ / PhH, reflux * \= 
86% 



138 



151 



O 




O 




Scheme 2-6 



For phenyl-substituted cyclopropane 138, its two C a -CP cyclopropane 
bonds (bond a and bond b) were not identical. When this cyclopropane 
fragmented, two products 152a and 152b could form, as shown in Scheme 2- 
7. Secondary radical 152b is strongly stabilized by a phenyl substituent and is 
therefore much more stable than primary radical 151a. Because the 
cyclopropane rotated freely, bonds a and b had the same orbital overlap with 



29 



the sp^-like orbital of ketyl radical 152. Thus, stereoelectronic influences were 
absent in this fragmentation. 51 As a result, this fragmentation was controlled by 
radical-stability effects, selectively yielding 151. 




Scheme 2-7 



LUMO 



LUMO 



I V 

\ \ A A / » 

•4^4- -h / 

SOMO SOMO'-f-'' 

h >^<h if* ^ H > ^ < Ph 
bond a OSnBu 3 OSnBu 3 bond b 

Figure 2-2 

SOMO-LUMO interactions of O-stannyl ketyl with cyclopropane in 152 



A second way to understand the cyclopropane fragmentation of ketyl 
152 was through Mariano's FMO theory. 1 2,25k a favorable interaction between 
the SOMO of O-stannyl ketyl (bearing electron-donating OSnBu3) and the 



30 



LUMO of a cyclopropane a-bond is required for its cleavage to occur. A 
cyclopropane a-bond substituted with an EWG has a lower energy LUMO, 
whereas that substituted with an EDG has a higher energy LUMO. For 
cyclopropane 152, bond b carried EWG phenyl and had a lower LUMO than 
bond a. Since stereoelectronic influences were absent, a better interaction was 
achieved between the ketyl's SOMO and b's LUMO, as shown in Figure 2-2. 
Thus, b cleavage was favored in this freely-rotating cyclopropane substrate. 

To study the O-stannyl ketyl-promoted fragmentation of a cyclopropane 
fused in bicyclic or tricyclic systems, three such substrates (153, 154 and 155) 
were planned, as shown in Figure 2-3. 




153 154 155 

Figure 2-3 
The bicyclic and tricyclic substrates 





1) SOCI 2 

2) P, Br 2 > 

C0 2 H 3) MeOH* 
89% 

156 157 



CrO, 



Br 



quinoline 
C0 2 Me 99% 




C0 2 Me 



158 



Ac 2 
51% 





NaH, DMSO 
"C0 2 Me 35% C0 2 Me 
159 153 



Scheme 2-8 



31 



The preparation of 153 is shown in Scheme 2-8. The synthetic route to 
159 followed Lange's procedure. 52 Conversion of 156 to 157 was achieved 
in 89% yield by Hell-Volhard-Zelinsky reaction. Dehydrobromination of 157 in 
quinoline gave 158 in quantitative yield. Ally lie oxidation with chromium (VI) 
trioxide produced 159 in 51% yield. Sulfur ylide reaction transformed 159 to 
153 in 35% yield. 45 

Substrates 154 and 155 were prepared from commercial oc.p-unsatu- 
rated ketones 160 and 161 using sulfur ylides 45 as shown in Scheme 2-9. 




Scheme 2-9 

Bicyclic and tricyclic substrates 153, 154 and 155 possess a rigidly 
fused cyclopropane. Stereoelectronic requirements of orbital overlap are 
expected to govern these cyclopropane fragmentations. For each substrate, 
once O-stannyl ketyl forms, its sp 2 -\'\ke orbital has better overlap with bond a. 
Bond b, conversely, is almost orthogonal to this sp^-like orbital, as illustrated in 
Scheme 2-10. 53 - 54 



32 




Scheme 2-10 



On the basis of stereoelectronic effects, 51 bond a cleavage should 
predominate over bond b cleavage, and the a cleavage products (162a, 163a 
and 164a) should predominate in the fragmentations. For O-stannyl ketyl 162, 
stereoelectronic effects compete with radical-stability effects which favor bond b 
cleavage, due to the stabilization of 162b by the ester. Intermediate 162a may 
form kinetically, but the more stable ring-enlarged 162b would eventually 



33 



predominate in the equilibrium, because of the reversibility of cyclopropane 
fragmentation. 55 Thus, ring expansion could occur for substrate 153 under 
treatment of TBTH and AIBN. 




OSnBu 3 



TBTH, AIBN 



C0 2 Me 



PhH, reflux 
69% 




155 



TBTH, AIBN 



PhH, reflux 
86% 



C0 2 Me 



H TBTH, AIBN 

PhH, reflux 
76% 




164a 

Scheme 2-11 



167 



To examine if stereoelectronic effects or radical-stability effects would 
predominate in the cyclopropane fragmentations, the reactions of substrates 
153, 154 and 155 with TBTH and AIBN were performed. As shown in Scheme 
2-11, for ester-substituted cyclopropane 153, ring expansion product 165 
(69%) was exclusively yielded, revealing predominance of 162b in the 
fragmentation. Radical-stability effects overcame stereoelectronic effects for this 
substrate and bond b was selectively cleaved. For substrates 154 and 155, 



34 



bond a cleavage predominated and stereoelectronic effects-favored products 
166 (86%) and 167 (76%) were yielded. Apparently, the driving force for more 
stable bond b-scission products 163b and 164b was not sufficient enough to 
compete with stereoelectronic effects. Thus, it was clear that the significance of 
radical-stability effects mainly depended on the substitution pattern of the 
cyclopropane. An ester or similar radical-stabilizing group at the cyclopropane's 
CP position was required for radical-stability effects to predominate. Recently, 
Cossy reached a similar conclusion by studying the photochemical electron 
transfer-induced ring scission of cyclopropyl ketones. 54 

A unique cyclopropyl ketone, tricyclo[3.3.0.0 2 - 8 ]octan-3-one 168 (Figure 
2-4), strongly held our attention and curiosity. 35 Containing a geometrically 
defined a-ketocyclopropane component rigidly fused on parent diquinane, 168 
was perfect for examining the competition of stereoelectronic effects and 
radical-stability effects in O-stannyl ketyl-promoted cyclopropane scissions. 
Stereomodels of 168 showed that the rc-bond of the carbonyl forms a dihedral 
angle of approximately 25° with the C2-C8 a-cyclopropane bond a. 56 Bond a is 
geometrically disposed for better overlap with the adjacent rc-system than the 
C1-C2 a-cyclopropane bond b. 



O 




2 a 8 



7 



b 



2 




6 



168 



8 



7 



Figure 2-4 
Tricyclo[3.3.0.0 2 - 8 ]octan-3-one 



35 



Metal-associated ketyl-mediated cyclopropane fragmentation of 168 was 
investigated by Monti in 1969, using harsh lithium-liquid ammonia medium, as 
shown in Scheme 2-1 2. 56 Stereoelectronic effects governed this ring scission. 
The overall two-electron reduction selectively cleaved bond a, giving 169 and 
170 in a ratio of 20 to 1. 



o 




\^IJ NH 3 (liquid) 

168 169 

Scheme 2-12 




(20:1) 



170 



The examination of this cyclopropane fragmentation using TBTH and 
AIBN was planned. Prior to the work presented in this dissertation, it had not yet 
been clear whether O-stannyl ketyl would behave in an analogous manner. 
This O-stannyl ketyl-promoted fragmentation markedly differed from the lithium- 
ammonia redox process in mechanism. O-stannyl ketyl reacted by free radical 
pathway under mild conditions, relative to the dissolved metal reduction. 

The special merit of tricyclo[3.3.0.0 2 . 8 ]octan-3-one 168 in the synthesis 
of cyclopentanoid natural products was recognized in 1980 by Demuth and 
Schaffner. 57 They predicted that this tricyclic ketone would provide "versatile 
building blocks for the total synthesis of polycyclopentanoids and related 
compounds". 5 8 Since then, many natural compounds have been synthesized 
using this ketone as a key intermediate, 58 ' 60 including (-)-coriolin, 61 (-)- 
silphiperfol-6-en-5-one, 62 and (±)-modhephene. 63 

The preparation of tricyclo[3.3.0.0 2 . 8 ]octan-3-one 168 has been 
achieved by different routes, including metal carbene insertion reactions. 56 - 64 



36 



The route via oxa-di-rc-methane (ODPM) rearrangement of bicycle 171 is 
apparently expeditious, as shown in Scheme 2-1 3. 58 This rearrangement is 
easy to perform, by just simply irradiating the dilute solution of 171 in a triplet- 
sensitizing solvent, such as acetone or acetophenone. This photochemical 
rearrangement always gives very good yields. Racemic 171 could be readily 
enantiomerically separated by protecting the carbonyl with diethyl (R,R)-tartrate, 




175 176 177 

Figure 2-5 

The tricyclo[3.3.0.0 2 -8]octan-3-one substrates and 
their ODPM rearrangement precursors 



37 



separating the ketal diastereomers by chromatography, and then deprotecting 
the carbonyl through acidic hydrolysis. 58,59 Each enantiomer can be thus 
obtained in >98% e.e. (enantiomeric excess). This offers a synthetic approach 
for enantiomerically pure cyclopentanoid natural products. 

To study the O-stannyl ketyl-promoted cyclopropane fragmentation in 
tricyclo[3.3.0.0 2 ' 8 ]octan-3-one substrates, three substrates (172, 173 and 174) 
were planned, as shown in Figure 2-5. Using these compounds, the 
significance of radical-stability effects relative to stereoelectronic effects in the 
fragmentations could be examined. So could the influence of the C1- and C2- 
substituents to the reactions. 




178 181 

Scheme 2-14 



To synthesize the analogs of 176, well-documented double Michael 
addition was initially used. 65 Unfortunately, the starting molecules extensively 
polymerized (Scheme 2-14). Ethyl allenecarboxylate 180 was prepared 
according to Lang's procedure, as shown in Scheme 2-1 5. 66 Its low yield was 
due to the difficulty in removal of a large amount of solid Ph3PO byproduct 
before distillation. These double Michael approaches were abandoned. 



38 



Ph 3 P Br O 

^^° Et 99% 3 ^0 E t 
182 183 

1 ) Et 3 N (0.5 eq), CH 2 CI 2 C0 2 Et 

=C :— 



2) CHgCOCI (0.5 eq), CH 2 CI 2 H 

3) distillation, 17% 1g0 

Scheme 2-15 



Diels-Alder cycloaddition was chosen to synthesize 176 and 177, using 
trimethylsilyloxycyclodiene 185 and mono- or double-ester-activated acetylene 
as dienenophile. 67 Diene 185 was prepared in 87% yield from cyclohexenone 
178 by Rubottom's method, as shown in Scheme 2-1 6. 68 



O L O OTMS 




178 184 185 

Scheme 2-16 



The Diels-Alder reaction of 185 and dimethyl acetylenedicarboxylate 
(DMAD) 186 was carried out in refluxing toluene at 120°C. However, instead of 
bicyclic adduct 177, phenol 189 was obtained in 89% yield, as shown in 
Scheme 2-17. The formation of this phenol was rationalized with a retro Diels- 
Alder process occurring at the relatively high reaction temperature, through 
which ethylene was liberated. Aromaticity was the obvious driving force. 



39 

Similarly, the reaction of 185 with ethyl propiolate 190 in refluxing toluene 
produced phenol 191 in 95% yield, instead of desired bicycle 176. 



OTMS C0 2 Me 




185 



PhMe 
120°C 
C0 2 Me 89% 
186 



Me0 2 C 



TMSO 




C0 2 Me 



187 



H 2 C — CH 2 

► 

retro Diels-Alder 



TMSO^^^C0 2 Me HO^^^^C0 2 Me 



^*^C0 2 Me ^^X0 2 Me 
188 189 



OTMS H 




1) PhMe, reflux 



185 



2) H 3 + 
C0 2 Et 95% 
190 




C0 2 Et 



191 



Scheme 2-17 



In order to prevent the retro Diels-Alder process, the reaction of 185 and 
DMAD 186 was performed at a lower temperature (80°C in benzene). The 
Diels-Alder reaction worked very well, giving desired cycloadduct 177 in 61% 
yield, as shown in Scheme 2-18. Phenol 189 was still produced, but only as a 
minor product this time. 

The reaction of 185 and 190 was carried out in refluxing benzene for 2 
days. Adduct 176 was isolated in 35% yield, with retro-[4+2] product 191 as the 
major product. This cycloaddition then was performed in a sealed flask at 70- 



40 



75°C. After 7 days, 176 was afforded in 88% yield, with a small amount of 
phenol 191. 




185 190 176 



Scheme 2-18 



To improve the yields, these Diels-Alder reactions were attempted at still 
lower temperatures (0°C-60°C). Disappointingly, the reactions were too slow to 
be useful and the retro-[4+2] process still could not be completely suppressed. 
An effort to catalyze the cycloaddition with Lewis acid SnCU at -78°C was also 
unsuccessful. 



171 



hv 




1 ,3-acyl shift 



hv, triplet sensitizer 
► 

ODPM rearr. 




192 



168 



Scheme 2-19 



41 



With precursors 176 and 177 in hand, it was time to examine the ODPM 
rearrangement. 69 This bicyclo[2.2.2]octenone photorearrangement was first 
investigated by Givens in 1971. 70 As shown in Scheme 2-19, direct 
photochemical irradiation of bicyclo[2.2.2]octenone 171 afforded 1,3-acyl shift 
product 192, while triplet-sensitized irradiation gave ODPM rearrangement 
product 168. 58 > 59 




171 193 194 




194 192 

Scheme 2-20 



The mechanism of these photochemical rearrangements have been well- 
studied. 58 The 1,3-acyl migration is initiated by photolytic cc-cleavage of the 
ketone to acyl-allyl diradical, which has the option of either regenerating the 
starting material or recombining in the alternative allylic position and forming 
1,3-shift product 192, as shown in Scheme 2-20. This reaction occurs from the 
n,7i* singlet excited state Si(n,n*) and also from the triplet excited state T2(n,7i*), 
as indicated in Figure 2-6. 

ODPM rearrangement occurs from the lowest lying excited triplet state 
Ti (7t,7u*).58 Ej sens represents the excited-state energy of the selected triplet 
sensitizer. After the triplet sensitizer reaches its excited state by absorbing the 



42 



1 ,3-acyl ^ 
shift Si(n,ji*) 



^ sens 




1 ,3-acyl 
shift 



ODPM 

rearr. 



Figure 2-6 

Energy diagram of bicyclo[2.2.2]octenone 171 




171 



O 




triplet 
sensitizer 



195 



197 197 

Scheme 2-21 



O 




196 



168 



irradiation energy hv, the sensitizer delivers and unloads energy ET sens to 
bicyclo[2.2.2]octenone 171. If the energies of T-|, T2 and Ei sens have been 
carefully adjusted by choosing the right triplet sensitizer and optimizing the 
irradiation wavelength and enone concentration, the ET sens can be set exactly 
between T2 and Ti . In this case, energy ET sens is exclusively transferred from 
the sensitizer to bicyclo[2.2.2]octenone*s Ti to secure ODPM rearrangement to 
occur.58 n -excited enone 171 can be expressed by diradical 195, as shown 
in Scheme 2-21. The carbon-centered radical adds onto the alkene to form 



43 



cyclopropane-separated diradical 196. The oxygen-centered radical cleaves 
the cyclopropane to give 197, where coupling of the two carbon-centered 
radicals yields tricyclic ketone 168. This photochemical sequence is termed 
"oxa-di-7c-methane" or "ODPM" rearrangement. 58 

The two best reaction conditions for an efficient ODPM rearrangement 
have been reported to be: 1) acetone as the sensitizer and solvent, enone 
concentration less than 2%, X\rr =300nm; 2) acetophenone as the sensitizer, 
pure acetophenone or 20% acetophenone in acetone, benzene or cyclohexene 
as the solvent, enone concentration less than 10%, A-irr >340nm. 59 The 
advantage in acetone serving as sensitizer is the ease in workup and isolation 
of the product, due to the low boiling point (56°C) of acetone. However, the 
enone concentration should not exceed 2% in acetone; otherwise the direct 
energy absorbance of the enone will become noticeably competitive, giving 1 ,3- 
acyl shift byproduct 192. When acetophenone serves as sensitizer at >340nm, 
the direct enone absorbance is negligible, and the enone concentration can be 
as high as 10%. The negative side of acetophenone is the difficult removal of 
this compound (boiling point 202°C), after the rearrangement is complete. 

A 450W Hanovia medium-pressure mercury-vapor lamp was used to 
irradiate the ODPM rearrangement precursors. In order to match the literature 
wavelength mentioned above, the irradiation was conditioned with a Pyrex 
glass filter. Pyrex glass is capable of absorbing most of the <320nm irradiation. 

To compare the efficiency of acetone and acetophenone as sensitizer, 
ODPM rearrangement was performed using a 0.08M solution of 177, as shown 
in Scheme 2-22. When acetone was used, the photorearrangement was 
complete in 24 hours, smoothly affording 174 in 83% yield. When 
acetophenone was the solvent and sensitizer, the reaction finished in 12 hours. 
After most acetophenone was distilled away, the residue was chromatographed 



44 



to separate the remaining acetophenone and rearrangement product. Tricyclic 
174 was isolated in 92% yield. Obviously, acetophenone was a more efficient 
sensitizer for ODPM rearrangement, giving higher yield in shorter irradiation 
time. However, due to the tedious acetophenone separation, acetone was 
preferred as our triplet sensitizer. 



Me0 2 C 



C0 2 Me 



C0 2 Me 
|C0 2 Me 



hv, Pyrex filter q. 





triplet sensitizer 






177 


0.08M 


174 


sensitizer & solvent 


irradiation time 


isolated yield 


acetone 
acetophenone 


24hrs 
12hrs 




83% 
92% 



Scheme 2-22 




176 173 

Scheme 2-23 

The ODPM rearrangement of 176 was accomplished in 84% yield after 
24-hour irradiation in acetone, giving tricyclic substrate 173. The yield was 
improved to 88% when 176 was irradiated for 48 hours, as shown in Scheme 
2-23. 

The preparation of C1-alkyl-substituted substrate 172 (Figure 2-5) 
started directly from 173, as shown in Scheme 2-24. Tricycle 173 was reduced 



45 



using excess amount of diisobutylaluminum hydride (DIBAH, 5 equivalents) to 
diol 198 in 99% yield. The primary hydroxy group was selectively protected 
with 1.2 equivalent of t-butyldiphenylsilyl chloride (TBDPSCI). Oxidation of 
secondary alcohol 199 to ketone 172 was done with PCC in 70% yield. 
Bearing t-butyldiphenylsiloxymethyl at its C1 position, compound 172 was 
suitable for studying the influence of C1-alkyl on the O-stannyl ketyl-promoted 
tricyclo[3.3.0.0 2 ' 8 ]octan-3-one fragmentation. Thus, substrates 170,171 and 
172 planned in Figure 2-5 were all synthesized. 




199 172 

Scheme 2-24 



Bu 3 SnO 




Figure 2-7 

O-stannyl ketyl of tricyclo[3.3.0.0 2 > 8 ]octan-3-one 



46 



For tricyclo[3.3.0.0 2 ' 8 ]octan-3-one substrates, once O-stannyl ketyl 200 
forms, bond a (C2-C8) has better overlap with the ketyl's sp^-like orbital than 
bond b (C1-C2) does, as shown in Figure 2-7. Thus, stereoelectronic effects 
favor bond a cleavage in the fragmentation. 35 

The reactions of tricyclic substrates 172, 173 and 174 with TBTH and 
AIBN in refluxing benzene are shown in Scheme 2-25. 35 Tricyclic 172 
(RC1=alkyl) afforded bond a cleavage product 202 in 83% yield in 4 hours. 
Ester 173 (Rci=ester) gave a single diastereomer 204 in 88% yield in 1 hour. 
When the reaction time was extended to 5 hours, the yield was improved to 
94%. Interestingly, diester substrate 174 (Rd=RC2=ester) produced only bond 
a cleavage product 206 in 59% yield, though its C1 -ester function was capable 
of stabilizing the radical formed by bond b cleavage. It was contradictory that 
174's C1 -ester did not play a role in the cyclopropane fragmentation, while 
173's C1 -ester apparently overwhelmed stereoelectronic effects. 35 Substrates 
173 and 174 differed only by the presence of an additional ester group at the 
C2 position of 174. 

Unequivocal confirmation of the product structures shown in Scheme 2- 
25 was required. Structure 204 had C2 symmetry, possessing 3 pairs of 
identical carbon atoms. Its 13 C NMR (nuclear magnetic resonance) spectrum 
clearly supported this C2 symmetrical structure. Only 8 carbon peaks were 
recorded in the spectrum. Obviously, the 3 pairs of carbon atoms only gave 3 
single peaks due to the identical chemical shift of the two individual carbon 
atoms in each pair. To desymmetrize 204 and observe all the carbon peaks, it 
was converted to 2,4-dinitrophenylhydrazone derivative 207, as shown in 
Scheme 2-26. Now there were three additional carbon peaks appearing in the 
NMR spectrum. Thus, the symmetrical structure of 204 was confirmed. 



47 




174 205 206 

Scheme 2-25 




The structural assignment of 204 was determined on the basis of proton 
NMR analysis and comparison with the spectra of known structurally-similar 
compounds 208L and 208R reported by Yates and Stevens. 71 The two 
possible structures of 204 are given in Figure 2-8: 204L and 204R. Inspection 
of a molecular model of 204L showed that the dihedral angle between C1-H or 



48 



H \8^C0 2 Me 




HO a \ H 
C0 2 Me 

208 L 

C8-H: 5 2.86, singlet 

H v£-C0 2 Et Et °2 C >s8^H 
H- 






HO a \ H 
C0 2 Me 

208R 

C8-H: 6 2.67, triplet, J=4Hz 
C0 2 Et 



0^3 4 " H 0^3 7 "H 

204L 204R 

C8-H:8 2.77, singlet 



H 



Bu 3 SnO 




H 



Figure 2-8 
The structural assignment of 204 



C5-H and C8-H bonds was about 90°, which would result in negligible coupling 
between the C8-H and the C1/C5-H. 71 > 72 A molecular model of 204R showed 
that the corresponding dihedral angle was 45°, which would result in the 
splitting of the C8-H signal into a triplet with coupling constant J of about 4 
Hz. 71 - 72 The observed 204's C8-H resonance was a singlet at 2.77 ppm. This 
signal was in nice agreement with that of structurally-similar 208L (singlet at 
2.86 ppm). This indicated that 204L was the single diastereomer produced in 
the cyclopropane fragmentation of 173. 

Thus, excellent stereoselectivity in the hydrogen abstraction from TBTH 
was achieved for radical intermediate 203 (Figure 2-8). TBTH could approach 
the C8 radical site from the L face or the R face. Due to the presence of flat 
tin(IV) enolate, the L face was much more sterically open than the R face. 
Therefore, TBTH selectively approached from the L face to afford 204L. 



49 



To confirm the presence of radical intermediate 203 in the cyclopropane 
fragmentation, the reaction of 173 and tributyltin deuteride (TBTD) was 
performed to trap out this intermediate by deuterium abstraction, as shown in 
Scheme 2-27. Symmetrical 204D was isolated in 78% yield. Comparison of the 
1 H and 13 C NMR spectra of 240D and 240 indicated that the deuteration 
occurred at C8 position of 240D. Key intermediate 203 was thus confirmed. 




209 210 

Scheme 2-28 



Surprisingly, when excess amount of AIBN was used in the reaction of 
173 and TBTH, nitrile 210 was obtained in quantitative yield, as shown in 
Scheme 2-28. This nitrile arose from the coupling reaction of intermediate 203 



50 



with cyanoisopropyl radical, formed in thermal decomposition of AIBN (Scheme 
1-1). It was interesting that 203 coupled faster with cyanoisopropyl radical than 
abstracting a hydrogen from TBTH. The formation of 210 also confirmed 
presence of 203. The participation of cyanoisopropyl radical in free radical 
reactions is known in literature. 140 




. l3 n, wi l2 ui 2 V- — inr v^^*^ 

-20°C, 3 hrs 70°C 

212 213 

Scheme 2-29 



The structure of cyclopropane-opening product 206 needed to be 
confirmed. The spectroscopic evidence was not conclusive for this structure, 
because the diester ketone product was complicated by an equilibrium mixture 
with its tautomer 206T. Both were clearly visible on the NMR time scale. To 
conclusively confirm the structure, the C3-carbonyl was removed using a three- 
step sequence illustrated in Scheme 2-29. The 206/206T mixture was reduced 
to alcohol 211 with sodium borohydride at -78°C. The alcohol was activated 
using mesyl chloride at -20°C. Elimination of 212 with 1,8-diaza- 
bicyclo[5.4.0]undec-7-ene (DBU) in refluxing THF afforded 213 as the sole 
isolable product. The 13 C NMR and the attached proton test (APT) study for 
213 revealed presence of 4 quaternary carbons (176.6, 164.6, 137.6, 65.7 



51 



ppm), 2 CH units (144.8, 49.4 ppm), 4 CH2 units (39.7, 35.6, 35.4, 26.1 ppm) 
and 2 CH3 units (52.2, 51.5 ppm) in this compound. These NMR data 
conclusively confirmed the assigned structure of 21 3. 35 




215b 

Scheme 2-30 



To explain the contrasting cyclopropane fragmentation results from very 
similar structures in Scheme 2-25, it was proposed that stereoelectronic effects 
initially favored the cleavage of bond a in all three precursors (172, 173 and 
174), and 215a initially formed in each case, as shown in Scheme 2-30. 35 It 
was proposed that a reverse reclosure also involved, though cyclopropane 
scission occurred at a much higher rate to release ring strain. If R2=H, as in 172 
and 173, the reclosure was more facile, because no substituent was present at 
C2 to sterically hinder this center. At this point, cleavage of bond b was likely to 
occur if there was a sufficient driving force. For 173 (Ri=C02Et), the driving 
force of radical-stability effects was significant enough to cleave bond b, 
because its C1 -ester could much stabilize radical 215b (i.e. 203). Once this 



52 



radical was stabilized, the reverse reclosure was energetically unfavorable and 
less likely. Radical 203 thus remained until hydrogen abstraction from TBTH 
occurred to give 204. 

Substrate 172 (Ri=CH20TBDPS) lacked radical-stabilizing substituent 
at its C1 position. Though the a cleavage was reversible, there was no driving 
force for the cyclopropane scission to proceed by the stereoelectronically- 
unfavored bond b cleavage pathway. Thus, radical 215a (i.e. 201) underwent 
hydrogen abstraction from TBTH, yielding 202 after hydrolysis. 

Diester substrate 174 (Ri = R2=C02Me) was different. After the 
stereoelectronically-favored bond a cleavage occurred initially, the R2-ester 
group sterically blocked the reclosure of radical 215a (i.e. 205) to 215. Similar 
rate-retarding effects by blocking 5-hexenyl radical cyclization at the internal C5 
position of the alkene have been well-established. 1 But they are not yet well- 
understood for 3-butenyl radical cyclizations. It is further noteworthy that if 
R2=C02Me, as in the case of 174, the reclosure prevents conjugation of the 
ester with the olefin, which is also energetically less favorable. Thus, 205 was 
the cyclopropane fragmentation product, giving 206 after hydrogen abstraction 
from TBTH and hydrolysis. 

In conclusion, the O-stannyl ketyl-promoted cyclopropane fragmentations 
were studied using various substrates: simple cyclopropanes, cyclopropanes 
fused on other rings, and tricyclo[3.3.0.0 2 >8]octan-3-ones. These ketyl-mediated 
fragmentations are governed by both stereoelectronic effects and radical- 
stability effects. The significance of the latter effects depends on the substitution 
pattern of the cyclopropane. These studies enable us to apply the cyclopropane 
fragmentations to organic synthesis, which is the subject of next chapter. 



CHAPTER 3 

APPLICATIONS OF THE O-STANNYL KETYL-PROMOTED 
CYCLOPROPANE FRAGMENTATIONS TO THE 
SYNTHESIS OF TRIQUINANE COMPOUNDS 

New methods for the construction of condensed cyclopentanoid ring 
systems (polyquinanes) continue to be developed at an accelerated pace since 
the 1970s. 60 Among important naturally occurring polyquinanes are tricyclic 
polyquinane sesquiterpenes, which are termed "triquinanes" and can be 
classified as linear, angular or propellane according to ring fusion (Figure 3- 
1).73a Triquinanes come from a wide variety of natural sources and many 
possess significant antibiotic and/or antitumor activity. 733 These structurally 
interesting triquinane natural products provide a particular vehicle for the 
application of various new cyclopentanoid synthetic methodologies. 60 



There are more than 40 different triquinane terpenes found in the 
nature. 74 Figure 3-2 shows the structures of several natural triquinanes. Among 
them, linear triquinane capnellene (216), hirsutic acid (217) and coriolin (218) 
have three cyclopentane rings linearly cis,anti,cis fused in a straight chain. 




linear 



angular 



propellane 



Figure 3-1 

The skeletons of triquinane compounds 



53 



54 



Angular triquinane subergorgic acid (219) and isocomene (220) possess three 
cyclopentane rings cis,anti,cis fused in an angled array. Modhephene (221) is 
a propellane triquinane. 




subergorgic acid (219) isocomene (220) modhephene (221) 

Figure 3-2 
Several natural triquinane compounds 

The field of triquinane synthesis has greatly expanded since hirsutic acid 
216 was first synthesized in 1974 by Matsumoto. 75 Numerous synthetic routes 
were attempted, and every major naturally occurring triquinane has been 
successfully prepared in organic labs. 60 - 74 Many triquinanes have even 
several syntheses using a variety of approaches, such as the compounds listed 
in Figure 3-2. 

Among the powerful approaches for triquinane synthesis is a free radical 
tandem cyclization sequence to construct two new cyclopentanes fused on the 
parent cyclopentanoid substrate in a single transformation. This synthetic route 
was elaborated by Curran and coworkers. 73 In this route, a bromide or iodide 



55 



must be properly placed in the cyclization precursor. With treatment of TBTH 
and AIBN, this bromide or iodide produces a reactive free radical (222 and 
225), which cyclizes onto a cyclopentene to form a bicyclic diquinane radical 
(223 and 226), as shown in Scheme 3-1. 73e This new radical then cyclizes 
onto a tethered olefin or alkyne to produce a linear (224) or angular (227) 
triquinane skeleton. One such example is Curran's synthesis of hirsutene 229, 
as shown in Scheme 3-2. 73a - D For this linear triquinane synthesis, the trans 
stereochemistry of the two tethers in radical reaction precursor 228 is essential 
for accomplishment of the naturally-occurring cis,anti,cis ring fusion in the 
tandem cyclization sequence. 




222 223 224 




225 226 227 



Scheme 3-1 



H 




TBTH 

AIBN* 

64% 




H 



228 



229 



Scheme 3-2 



56 



One main drawback of Curran's approach is that too many steps are 
usually required to prepare the tandem cyclization precursor. For example, a 
12-step synthesis was used to synthesize precursor 228 in Curran's route for 
hirsutene 229. 73a > D All these steps were directed to setup the combination of a 
multiple-bond tether and a diquinane radical (223 or 226). 

Chapter 2 has reported our studies on the O-stannyl ketyl-promoted 
cyclopropane fragmentations. The fragmentation of tricyclo[3.3.0.0 2 -8]octan-3- 
one substrates selectively gives the bond a (C2-C8) cleavage product, unless a 
radical-stabilizing substituent is at the C1 position. As shown in Scheme 2-25, 
the cyclopropane fragmentations of 172 and 174 produced diquinane radicals 
201 and 205, which could be utilized to achieve triquinane synthesis. 

To thus accomplish triquinane synthesis on the basis of our previous 
studies, a novel O-stannyl ketyl-promoted cyclopropane fragmentation- 
cyclization tandem sequence was envisioned. As illustrated in Scheme 3-3, if 




232 233 

Scheme 3-3 



an olefin or alkyne tether was placed at C7 (230), after the cyclopropane 
fragmentation, the cyclization of diquinane radical 232 would yield linear 



57 



triquinane 233. If the tether was placed at C1 (234), the radical cyclization 
would produce angular triquinane skeleton 237 (Scheme 3-4). This work would 
generate a new general approach towards the synthesis of triquinane 
compounds by taking advantage of tricyclo[3.3.0.0 2 - 8 ]octan-3-ones. Compared 
to Curran's general route, this approach could reach the final triquinane 
cyclization stage in a shorter and more efficient manner. Much of this simplicity 
could be found in the use of a ketone (230 or 234) to initiate the radical 
process, rather than a halide. 




Figure 3-3 

The model precursors for cyclopropane fragmentation- 
cyclization sequence and triquinane skeleton synthesis 



58 



To examine this O-stannyl ketyl-promoted cyclopropane fragmentation- 
cyclization tandem sequence and demonstrate this new triquinane synthesis 
approach shown in Schemes 3-3 and 3-4, two model precursors 238 and 239 
were planned, as exhibited in Figure 3-3. 36 > 37 Note that they differ primarily by 
placement of the olefin tether. 

To synthesize precursor 239 from 1-ethoxycarbonyltricyclo[3.3.0.0 2 ' 3 ]- 
octan-3-one 173, which had been prepared in chapter 2, the route shown in 
Scheme 3-5 was initially planned. Tricycle 173 was reduced to diol 198 with 
excess DIBAH. Oxidization to dicarbonyl 240 with PCC was achieved in 52% 
yield for these two steps. To finish the preparation of 239, it was attempted to 
take advantage of the reactivity difference between a ketone and a presumably 



C0 2 Et r ° H 
Q^/^|7\ DIBAH (5 eg ) H Q^/\ 7\ PCC m 
CH 2 CI 2 \^ J CH 2 CI 2 



-78°C-r.t 



52% from 173 



173 198 

CHO H0 V\/ 
a MgBr Y 

° A/ 0-1 eg) \/ o ^ T\ 

\\J THF, -78°C A * \\J 

240 239 

Scheme 3-5 

more reactive aldehyde by treatment with 1 equivalent of allyl Grignard reagent. 
Disappointingly, the reactivity difference between the ketone and aldehyde 
carbonyls in 240 was negligible and the selectivity in this addition was very 
poor. Even when 1.1 equivalent of allylmagnesium bromide was added 
dropwise to a very dilute 240 solution (0.1 M) at -78°C, double-Grignard- 



59 



addition product was still obtained along with remaining unreacted 240. In 
order to add an allyl unit to the aldehyde, the ketone had to be protected before 
the Grignard reaction. Thus, our synthetic approach was modified to that shown 
in Scheme 3-6. 36 



C0 2 Et HO a 

V OH 



\ 7 PPT S(cat.) 
^ — PhH, reflux 
173 Dean-Stark, 90% 

OH 

PDC 



q C0 2 Et 




241 



DIBAH (2.1 eg ) 

CH 2 CI 2 , -78°C 
96% 



HQ 




CHO 



CH 2 CI 2 o' 
67% 

242 243 




i,A/' 



MgBr 



2)H 3 + \JJ (1.3:1) 



85% 



239 



Scheme 3-6 



Protection of the ketone carbonyl of 173 using ethylene glycol and mild 
catalyst PPTS (pyridinium p-toluenesulfonate) gave ketal 241 , as shown in 
Scheme 3-6. A Dean-Stark tube was attached to the reaction flask. This 
protection was complete in 12 hours in 90% yield. To reduce the C1 -ester group 



C0 2 Et 




DIBAH (4 eq) 
► 

CH 2 CI 2 , 
-78°C-r.t. 




241 



242 



244 



Scheme 3-7 



60 



of 241, 4 equivalents of DIBAH were used in the first attempt. Interestingly, the 
ketal protective group was reductively cleaved by the excess amount of DIBAH 
remaining after the ester reduction had been complete, and diol 244 was 
isolated in 71% yield (Scheme 3-7). Similar reductive cleavages of ketals and 
acetals by hydride donors are known in literature. 76 

In next attempt, only 2.1 equivalents of DIBAH were added to 241 at 
-78°C, as shown in Scheme 3-6. Primary alcohol 242 was yielded in 96% yield, 
and no overreduced product 244 was found. To oxidize 242 to 243, PCC was 
initially used. However, during the oxidation, the ketal protection group was 
cleaved. Dicarbonyl 240 was obtained as the major product in 67% yield, while 
243 was isolated in a yield less than 5% (Scheme 3-8). This carbonyl 
deprotection was rationalized by the acidity of the PCC reagent. 




242 240 (67%) 243 (<5%) 

Scheme 3-8 



To avoid the deprotection, a slightly basic oxidant pyridinium dichromate 
(PDC) was used, oxidizing 242 smoothly to desired ketal aldehyde 243 in 67% 
yield, as shown in Scheme 3-6. The allyl tether was added to the aldehyde 
through a Grignard reaction. The ketal protective group was removed during the 
normal Grignard acidic workup, giving precursor 239 in 85% yield. The GC 
ratio of the two 239 diastereomers was 1 .3 to 1 . These two diastereomers were 
not separable from each other by column chromatography. 



61 



Now it was time to examine the proposed O-stannyl ketyl-promoted 
cyclopropane fragmentation-cyclization sequence and angular triquinane 
synthesis approach (Scheme 3-4). Refluxing 239 in benzene at a concentration 
of 0.1 M for 14 hours, with 2 equivalents of TBTH and 1 equivalent of AIBN, 
smoothly furnished angular triquinane 245 in 94% yield, as shown in Scheme 
3-9. The GC ratio of the major cyclization products (the C1 1-diastereomers) and 
the minor cyclization products was 57:1. The GC ratio of the 245 C11- 
diastereomers was still 1.3:1. 36 




Scheme 3-9 



NMR was used to establish the stereochemistry of triquinane 245 at the 
C9 center. Based on Whitesell's 13 C NMR studies, 77 if the C9-methyl was 
endo, the C9 resonance should be around 15 ppm and the C8 resonance 
should be around 33.0 ppm (for endo C1 1-OH) and 35.4 ppm (for exo C1 1-OH). 
If the C9-methyl was exo, the C9 resonance should be around 19 ppm and the 
C8 resonance should be around 37.4 ppm (for endo C11-OH) and 39.8 ppm 
(for exo C11-OH). The 13 C NMR spectrum of 245 clearly indicated that for the 
major cyclization products, the C9-methyls were at 14.5 and 14.6 ppm, and the 
C8-tertiary centers appeared at 31.0 and 33.2 ppm. These characteristic 13 C 
NMR peaks were in excellent agreement with those calculated for the endo-C9- 
methyl stereomers by Whitesell's method. Thus, the C9-methyl stereochemistry 
of the major products 245 was established as endo. 



62 



Excellent stereochemical control was realized in the O-stannyl ketyl- 
promoted cyclopropane fragmentation-cyclization sequence shown in Scheme 
3-9, where the C9-methyl endo:exo stereoselectivity was 57:1 in the 5-exo-trig 
radical cyclization. Beckwith's chair-like transition state 246-247 explains the 
endo-C9-methyl stereochemistry in 245, as shown in Scheme 3-1 0. 16 - 17 - 36 




247 248 

Scheme 3-10 



In order to finally obtain a single triquinane diastereomer and simplify 
characterization, PCC oxidation was performed to remove the C11 sp 3 
stereocenter of 245. The oxidation was complete in 1 hour, producing angular 
triquinane diketone 249 in 78% yield, as shown in Scheme 3-11. In the 13 C 
NMR of 249, the C9-methyl was at 16.2 ppm and the C8 at 30.1 ppm. According 
to WhiteselPs studies, 77 if the C9-methyl was endo, it should appear at about 
15 ppm and the C8 at 30.1 ppm; if the C9-methyl was exo, it should be around 
19 ppm and the C8 at about 34.5 ppm. The 13 C NMR resonance for 249 was in 
excellent agreement with that calculated for the endo-C9-methyl stereoisomer. 
The endo stereochemistry of the C9-methyls in 245 and 249 was reconfirmed. 



63 




245 249 

Scheme 3-1 1 

This study examined the O-stannyl ketyl-promoted cyclopropane 
fragmentation-cyclization tandem sequence and a novel approach for angular 
triquinane synthesis. Excellent stereoselectivity was accomplished. It is worth 
noting the efficiency of this new method. The entire synthetic sequence is very 
efficient, producing triquinane 245 in 5 steps in 46% overall yield from 173, 
which can be prepared in 3 steps in 67% overall yield from 2-cyclohexen-1-one 
178. 

To synthesize precursor 238, which could lead to construction of a 
model linear triquinane and another example of O-stannyl ketyl-promoted 
cyclopropane fragmentation-cyclization sequence, the approach shown in 
Scheme 3-12 was planned. 37 




Scheme 3-12 



64 



Starting material c/s-1 ,5-dimethylbicyclo[3.3.0]octane-3,7-dione 250 was 
prepared using Weiss condensation, 78 a s shown in Scheme 3-13. The 2:1 
condensation of dimethyl 1 ,3-acetonedicarboxylate 253 and 2,3-butanedione 
254 was carried out in an aqueous buffer solution of sodium bicarbonate (pH 
8.3). Condensation product 255 gradually formed and separated from the 
solution as white solid in 88% yield. The mechanism of this 2:1 condensation 
has been discussed by Cook. 79 Hydrolysis of 255 in a refluxing aqueous 
mixture of HCI and HOAc yielded bicyclic dione 250 in 99% yield. 



Me0 2 C 

C0 2 Me 

NaHC0 3 (aq.) 

O ►nU 





254 



pH 8.3 
C0 2 Me 88% 

253 




255 



HCI, HOAc, H 2 O 
► 

reflux, 99% 




=0 



250 



Scheme 3-13 



To prepare tricyclic dione 252, Gleiter's method was first used, as shown 
in Scheme 3-1 2. 80 Diketone 250 was monobrominated by adding 1.4 
equivalent of CuBr2 to the refluxing reaction mixture. Copper(ll) bromide had to 
be added very slowly in a very little amount each time, otherwise multiple- 
bromination products would predominate. Monobromide 251 was produced in 
46% yield. Because of the cup-like shape of molecule 250, bromide 
approached primarily from the exo face, and so the bromide stereochemistry in 
251 was exo. Treatment of 251 with 1.1 equivalent of DBU smoothly furnished 



65 



symmetrical tricyclic dione 252 in 72% yield. 80 In this reaction, only the 
deprotonation at one position could result in dehydrobromination, constructing 
the fused cyclopropane unit in dione 252. 

In order to improve the yield of 252, iodination of 250 was attempted. 
Barluenga's methodology was used to prepare iodide 256, as shown in 
Scheme 3-1 4. 81 Iodide 256 was not characterized and purified. Crude iodide 
256 was directly used to produce 252 in 51% yield for these two steps. Thus, 
the yield for 252 from 250 was increased from 33% (CuBr2 method) to 51%. 




51% for 2 steps 

252 

Scheme 3-14 




Scheme 3-15 



66 



Horiuchi's iodination methodology was also attempted, as shown in 
Scheme 3-15.82 However, this iodination method was so messy that several 
unknown side products also formed. Solvent acetic acid was difficult to remove. 
The two-step yield from 250 to 252 was only 25%, much lower than that by 
Barluenga's iodination method (Scheme 3-14). 

The preparation of precursor 238 was straightforward from tricyclic 
ketone 252, as shown in Scheme 3-12. Addition of 1.3 equivalent of 3- 
butenylmagnesium bromide to 252 at -78°C afforded 238 in 64% yield. 
Because of its cup-like molecule shape, the incoming Grignard reagent could 
approach 252's carbonyls only from the exo face. This exo:endo face selectivity 
was >1 00:1 by GC. This stereoselective addition of the Grignard reagent to the 
most accessible exo face was important for later elaboration to the cis,anti,cis- 
configuration of the model linear triquinane skeleton. Due to the C2 symmetry of 
252, same addition product was obtained no matter which carbonyl group 
reacted. 

O-stannyl ketyl-promoted cyclopropane fragmentation-cyclization tandem 
sequence using precursor 238 was examined, as shown in Scheme 3-1 6. 37 
Refluxing 238 in benzene at a concentration of 0.25 M overnight, with 3 
equivalents of TBTH and 1 equivalent of AIBN, gave linear triquinane 259 in 
83% yield. The exo stereochemistry of the olefin tether in 238 secured the 
requisite c/s,anf/,c/s-configuration in 259, which occurs in all natural linear 
triquinane compounds. The newly formed C9-methyl (13.7 ppm in 13 C NMR) 
was established as endo for the major product, by comparison with 13 C NMR 
studies of closely related fused-cyclopentanes. 77 If the C9-methyl was endo, its 
resonance should be around 15 ppm. If it was exo, its resonance should be at 
about 20 ppm. 77 This C9-methyl endo:exo stereoselectivity in the 5-exo-trig 
radical cyclization was 4:1 by GC. This endo-C9-methyl stereoselectivity can be 



67 



explained using Beckwith's chair-like transition state 257-258, as shown in 
Scheme 3-16. 16 > 17 . 37 




In conclusion, it is demonstrated that the O-stannyl ketyl-promoted 
cyclopropane fragmentation-cyclization tandem sequences work very well. 
These sequences are highly stereoselective and the stereochemistry of their 
products can be predicted with accuracy. The yields of these sequences are 
excellent, considering the complexity of their products. Through these two 
examples, a novel and efficient synthetic approach toward angular and linear 
triquinane compounds is demonstrated. The work in this chapter marked the 
first real synthetic application of the O-stannyl ketyl-promoted cyclopropane 
fragmentations and enhances our understanding and knowledge of O-stannyl 
ketyl radicals. 



CHAPTER 4 

OTHER INVESTIGATIONS OF THE O-STANNYL KETYL-PROMOTED 
CYCLOPROPANE FRAGMENTATIONS 



O-stannyl ketyl-promoted cyclopropane fragmentations were studied 
using a variety of substrates in previous chapters. In all the cases, after 
fragmentations, the radical centers were reduced by hydrogen abstraction from 
TBTH, and the tin(IV) enolates were hydrolyzed, though these radicals and 
enolates were synthetically useful. This chapter reports our preliminary results 
of application of the post-fragmentation tin(IV) enolates and trapping the post- 
fragmentation radicals with allyltributyltin. 

Applicatio n of the Post-Fragmentation TinflVl Enolates 

Tin(IV) enolates are useful intermediates and have been applied to many 
synthetic transformations. 6g,83 Recently Enholm demonstrated that tin(IV) 
enolates can be smoothly generated by the reaction of TBTH and <x,p- 
unsaturated ketones, 34 as illustrated in Scheme 1-23. These tin(IV) enolates 
function very well in aldol and alkylation reactions. 

It has been well known since early 1970s that O-stannyl ketyl-promoted 
cyclopropane fragmentations readily generate tin(IV) enolates 133, 25 " 27 as 
shown in Scheme 4-1. However, prior to the work described in this chapter, no 
synthetic exploration of this post-cyclopropane-fragmentation tin(IV) enolates 
had been reported. We envisioned that these tin(IV) enolates could be 



68 



69 



synthetically useful by reacting with an electrophile, such as an aldehyde, 
ketone or alkyl halide, forming a new carbon-carbon bond. 

O OSnBu 3 OSnBu 3 

R A^ _TBTH^ ^ . R Vs 

^ AIBN ^ H 

130 131 132 

O 




TBTH E + 



Bu 3 Sn. FT > R 




133 H 260 E H 

Scheme 4-1 



To examine synthetic application of these tin(IV) enolates, an aldol 
reaction was performed using cyclopropyl ketone 137. The cyclopropane 
fragmentation finished in 2 hours, monitored by TLC. At room temperature, 
benzaldehyde 262 was added to tin(IV) enolate 261 and the reaction mixture 




263E (4.4:1) 2 63T 



Scheme 4-2 



70 



was stirred overnight, giving 263E/263T in 97% yield as a mixture of erythro 
and threo diastereomers (4.4:1 by proton NMR integration), as shown in 
Scheme 4-2. The stereochemical assignment (erythro or threo) was made by 
1 H NMR, using the well-accepted Jthreo > Jerythro relationship. 84 For the 
major product, the coupling constant between the carbinol proton and the 
methine proton was 4.5Hz; for the minor product, the coupling constant was 
6.9Hz. Thus, the major product was assigned as erythro (263E). This 
assignment was confirmed by 13 C NMR spectra. According to Heathcock's 
studies, 85 the carbinol resonance of erythro p-hydroxycarbonyl compounds 
should be at 71.6-78.1 ppm and that of threo isomer should be higher at 74.0- 
82.5 ppm. The carbinol of the major product appeared at 73.8 ppm, while the 
carbinol of the minor product was at 75.6 ppm. The erythro assignment for the 
major product was thus confirmed. This is the first known O-stannyl ketyl- 
promoted cyclopropane fragmentation-aldol reaction. 

A similar aldol reaction of tin(IV) enolate 261 and cyclohexanecarbox- 
aldehyde 264 gave 265 in 92% yield, as shown in Scheme 4-3. A single 
diastereomer was isolated in excellent selectivity (>46:1 by GC). 




265 

Scheme 4-3 



71 



Alkylation reactions were also performed using tin(IV) enolate 261, as 
shown in Scheme 4-4. When the cyclopropane fragmentation finished in 2 
hours, 5 equivalents of HMPA were added at room temperature to increase the 
nucleophilicity of the enolate. 34c, d /\||<y I halide was next added and the mixture 
was refluxed overnight, giving alkylation product 267 (86%) and 268 (95%) in 
excellent yields. These are the first O-stannyl ketyl-promoted cyclopropane 
fragmentation-alkylation reactions. 




OSnBu 3 



TBTH 
AIBN 



PhH, 80°C _ 
MeO „. MeO 

137 2hrs 

1) HMPA (5 eq.) 



2) RX, reflux 



MeO 




RX alkylation product isolated yield 



V 



Br 



267 86°/c 



o 



vww 268 



95% 



o 



Scheme 4-4 

In a summary, tin(IV) enolates generated in the reactions of cyclopropyl 
ketones and TBTH are synthetically useful and work well in aldol and alkylation 
reactions. This exploration adds new depth to the O-stannyl ketyl-promoted 
cyclopropane fragmentations. 



72 

Cyclopropane Fragment ation-Allvlation bv Allyltributyltin 



Chapter 1 has introduced Keek's allylation reactions (Schemes 1-8 and 
1-9). 14 Historically, this allylation method dates back to 1973 when Migita and 
Pereyre first reported the free radical chain reaction of allylstannanes and 
organic halides. 86 | n these reactions, a free radical was trapped by an ally I 
group, and a new carbon-carbon bond formed between the radical site and the 
ally I unit, as shown in Scheme 1-8. The first systematic investigation of this 
reaction was published in 1975. 87 In 1982, Keck demonstrated that this 
allylation reaction worked well in complicated substrates, tolerating the 
presence of acetals, ketals, ethers, epoxides, lactones, free hydroxyl groups, 
esters and sulfonate esters. 143 Besides organic halides, Keck realized the 
allylation reactions of thioethers, thiocarbonyl esters and selenides. Keck found 
methallyltributyltin also suitable for this type of reaction. 140 




Scheme 4-5 



Since then, this allylation method has steadily found further 
investigations and synthetic applications. 88 For example, Keck applied it to the 



73 



synthesis of pseudemonic acid C, as shown in eq. 17 in Scheme 4-5. 88e 
Hanessian utilized this allylation method to prepare 6-a-allyl penicillanates 
272, as shown in eq. 18. 8 8f 

In 1985 Moriya applied allyltributyltin to radical cyclizations. 89 A typical 
free radical cyclization uses TBTH. The last step of this cyclization is reductive 
hydrogen abstraction by cyclized carbon-centered radical from TBTH. When 
allyltributyltin is used for cyclization, the hydrogen abstraction step is modified to 
a new carbon-carbon bond formation, without sacrificing the free radical chain 
process, as shown in Scheme 4-6. The chain process is maintained by 
regenerating tributyltin radical through an Sh2' reaction between cyclized 
radical 275 and allyltributyltin. Overall, an alkene-tethered ring 276 is 
produced in this reaction. 




275 276 

Scheme 4-6 



A similar cyclization was examined by Curran, as shown in Scheme 4- 
7. 90 Curran used acylsilane as a radical acceptor. After the 6-exo cyclization, 
radical 279 rearranged to 280 which finally reacted with allyltributyltin to 
produce 281 in 60% yield. 



74 




An interesting application of allyltributyltin is Mizuno's double vicinal 
carbon-carbon bond-forming reaction on electron-deficient alkenes by 
allyltributyltin and alkyl iodide, as shown in Scheme 4-8. 91 The mixture of 
dicyano alkene 282, allyltributyltin 29 and iodomethane 283 in 1 2:5 ratio was 
refluxed in benzene. The reaction was complete in 6 hours, affording 284 as 
the sole product in 85% yield. The allyl unit from allyltributyltin was 
regioselectively introduced to the a-carbon of dicyanoethene 282, and the 
methyl group from iodomethane 283 to the (3-carbon. This three-component 
coupling reaction inserted two different carbon-functional groups across a 
double bond in one step. 



Ph - Ph. XH 3 

AIBN 



+ Bu 3 s/^ + l-CH 3 



NC ^CN PhH, reflux ^ 

282 29 283 85% CN 284 

Scheme 4-8 



75 



In order to expand the application scope of O-stannyl ketyl-promoted 
cyclopropane fragmentations, allyltributyltin chemistry was combined with our 
cyclopropane fragmentation studies. The allyltributyltin-induced cyclopropane 
fragmentation was unknown prior to the work described in this chapter. This 
fragmentation-allylation reaction is illustrated in Scheme 4-9. The primary 
process is AlBN-initiated formation of tributyltin radical 5 from allyltributyltin 29. 
Radical 5 adds to the carbonyl of cyclopropyl ketone 130, giving O-stannyl ketyl 
species 131. The cyclopropane fragments to afford radical 132. This 
intermediate attacks allyltributyltin 29 to acquire its allyl unit through an Sh2' 
substitution and regenerate tributyltin radical 5 to continue the chain reaction. 
Fragmentation-allylation product 285 is thus produced. 




Scheme 4-9 



To examine this fragmentation-allylation reaction, ketones 137 and 171 
were refluxed with allyltributyltin and AIBN in benzene. The desired 
fragmentation-allylation products 286 (50%) and 287 (94%) were isolated, as 



76 

shown in Scheme 4-10. These are the first allyltributyltin-induced cyclopropane 
fragmentation-allylation reactions. 

O O 




Scheme 4-10 



The stereochemistry of 287 was assigned on the basis of the structure 
of 204L (Figure 2-8) and was confirmed by NOE (nuclear Overhauser effect) 
difference NMR spectrum. 92 Positive NOE difference was observed for the b- 
protons at C2 and C4 methylenes when the allylic methylene (C a ) protons were 
irradiated. Excellent stereoselectivity in the allyl abstraction from allyltributyltin 
was achieved for radical intermediate 203. This stereoselectivity could be 
rationalized with the steric difference between the L face and the R face of 203 
for approaching allyltributyltin molecule. 



77 



In a summary, the O-stannyl ketyl-promoted cyclopropane fragmentation- 
allylation works well using allyltributyltin. This reaction forms a new carbon- 
carbon bond by introducing an allyl unit. 

The preliminary study described in this chapter exhibits the duality of the 
free radical and tin(IV) enolate species generated in the O-stannyl ketyl- 
promoted cyclopropane fragmentations. Obviously, further synthetic efforts to 
capitalize on both species will definitely lead to exciting developments in this 
area. 



CHAPTER 5 
SUMMARY 



The studies described in this dissertation are an attempt to expand the 
realm of free radical chemistry. The mild reaction conditions and the ability to 
control the reactivity, stereoselectivity and regioselectivity in these reactions 
have made free radical methodologies valuable and indispensable in organic 
synthesis. Much current free radical chemistry has been dominated by halogen 
and group abstractions as the source of organic radicals. The halogen or group 
functionality is usually lost in these classical free radical reactions. The reaction 
of TBTH and carbonyls provides a unique O-stannyl ketyl radical, which 
behaves like a pseudo-protected cc-oxygen-functionalized radical. The original 
oxygen functionality is well preserved in its reactions, leading to alcohols or 
ketones. It makes O-stannyl ketyl radical especially attractive and provides 
advantages over classical free radicals. However, the O-stannyl ketyl chemistry 
is not well-understood yet, and its synthetic applications are still limited. The 
goal of this dissertation is to enhance our understanding of this ketyl species by 
studying the cyclopropane fragmentations and their synthetic applications. 

Chapter 2 examined the O-stannyl ketyl-promoted cyclopropane 
fragmentations using a variety of cyclopropyl ketone precursors. The 
fragmentations were governed by both stereoelectronic effects and relative 
stability of the fragmentation radical products. The significance of radical- 
stability effects depended on the substitution pattern of the cyclopropane. These 



78 



79 



studies enabled us to design synthetic methodologies to utilize the special 
merits of cyclopropane fragmentations. 

Chapter 3 demonstrated our O-stannyl ketyl-promoted cyclopropane 
fragmentation-cyclization tandem sequence. This was the first synthetic 
application of O-stannyl ketyl-promoted cyclopropane fragmentations. 
Triquinane terpenes had been among the most interesting and challenging 
natural products for synthetic chemists for over two decades. Their unique 
cis,trans,cis angularly- or linearly-fused tricyclopentanoid skeletons had served 
as a testing vehicle for a wide variety of synthetic methodologies. The 
cyclopropane fragmentation-cyclization sequence was examined in the 
synthesis of a model angular triquinane and a model linear triquinane. The 
synthesis was successful and efficient. Very good regioselectivity and 
stereoselectivity were accomplished in both tandem sequences. This study 
demonstrated a novel synthetic route to triquinane compounds. 

Chapter 4 reported preliminary results of two new investigations. The 
tin(IV) enolate formed in the cyclopropane fragmentations was examined. Its 
aldol and alkylation reactions were accomplished in excellent yield. The 
reaction of allyltributyltin with cyclopropyl ketones was performed. The O- 
stannyl ketyl-promoted cyclopropane fragmentation-allylation was successful. 
These preliminary results added new depth to O-stannyl ketyl chemistry and the 
cyclopropane fragmentation methodologies. 

Collectively, these studies have extended the understanding and 
applications of O-stannyl ketyl chemistry. This work has established the use of 
O-stannyl ketyl-promoted cyclopropane fragmentations in organic synthesis. 



CHAPTER 6 
EXPERIMENTAL 



General Methods 



Infrared spectra were recorded on a Perkin-Elmer 1600 FT-IR 
spectrometer and are reported in wave numbers (cm -1 ). 1 H NMR spectra were 
recorded on a Varian Gemini-300 (300 MHz) or a General Electric QE-300 (300 
MHz) spectrometer. 13 C NMR spectra were recorded at 75 MHz on the above- 
mentioned spectrometers. Chemical shifts are reported in ppm down field 
relative to tetramethylsilane as an internal standard in CDCI3. Elemental 
analysis was performed by the Atlantic Microlab Inc., Norcross, Georgia or by 
the Elemental Analysis Service at the Department of Chemistry, University of 
Florida, Gainesville, Florida. The high resolution mass spectroscopy (HRMS) 
was performed by the Mass Spectroscopy Service at the Department of 
Chemistry, University of Florida, Gainesville, Florida. 

All reactions were run under inert atmosphere of argon using oven dried 
apparatus. All yields reported refer to isolated material judged to be 
homogeneous by thin layer chromatography (TLC) and NMR spectroscopy. 
Solvents were dried according to established procedures by distillation under 
inert atmosphere from appropriate drying agents. 

Analytical TLC was performed with Aldrich Z1 2272-6 precoated silica gel 
plates (0.25 mm) using 254 nm UV light, p-anisaldehyde in ethanol with acetic 
acid or phosphomolybdic acid in ethanol as indicator. Column chromatography 



80 



81 



was performed using Merck silica gel 60 (230-400 mesh) by standard flash 
chromatographic techniques. GC experiments were performed on a Varian 
3500 capillary gas chromatograph using a J & W fused silica capillary column 
(DB5-30W; film thickness 0.25 u.). 

Experimental P rocedures and Results 

1-Dodecen-3-ol f1 41 ^ . Decyl aldehyde (5.00 g, 32.1 mmol) was dissolved in 
THF (50 ml_). This solution was chilled to -78°C. Vinylmagnesium bromide (1.0 
M in THF, 65.0 ml_, 65.0 mmol) was added to the solution dropwise through a 
syringe. The reaction was complete in 1 hour and quenched by ice chips and 
NH4CI (aq.). The mixture was extracted with ether. The ether phase was dried, 
rotovaped and subjected to flash column chromatography to give 141 (6.13 g, 
100%) as a clear oil. Rf (1:4 ether/hexane) 0.31. 1 H NMR 8 5.86 (m, 1H), 5.20 
(d, J=1 7 Hz, 1 H), 5.08 (d, J=1 1 Hz, 1 H), 4.08 (m, 1 H), 2.00 (s, 1 H), 1 .52-1 .50 (m, 
2H), 1.27 (m, 10H), 0.90-0.83 (m, 7H); 1 3c NMR 6 141.4, 114.3, 73.2, 37.0, 
31.9, 29.5 (3C), 29.3, 25.3, 22.6, 14.0. Anal. Calcd for C12H24O: C, 78.18; H, 
13.13. Found: C, 78.38; H, 13.16. 

1.6E-Dode cadien-3-ol (142V Tra/is-4-Decenal (1000 mg, 6.49 mmol) was 
dissolved in THF (13 ml_). This solution was chilled to -78°C. Vinylmagnesium 
bromide (1.0 M in THF, 13.0 ml_, 13.0 mmol) was added to the solution 
dropwise with a syringe. The reaction was complete in 1 hour and quenched by 
ice chips and NH4CI (aq.). The mixture was extracted with ether. The ether 
phase was dried, rotovaped and chromatographed to afford 142 (1194 mg, 
100%) as a clear oil. Rf (1:4 ether/hexane) 0.37. 1 H NMR 8 5.86 (m, 1H), 5.43 
(m, 2H), 5.22 (d, J=17 Hz, 1H), 5.10 (d, J=10 Hz, 1H), 4.11 (m, 1H), 2.11-2.05 
(m, 2H), 1.97 (m, 2H), 1.86 (d, J=4.5 Hz, 1H), 1.58 (m, 2H), 1.39-1.28 (m, 6H), 



82 



0.88 (t, J=7 Hz, 3H); 1 3c NMR 8 141.1, 131.2, 129.3, 114.5, 72.6, 36.7, 32.5, 
31.3, 29.2, 28.5, 22.5, 14.0. Anal. Calcd for C12H22O: C, 79.06; H, 12.16. 
Found: C, 79.11; H, 12.18. 

Preparation of 1-Dodecen-3-one (143) bv Swern oxidation . 48 Oxalyl chloride 
and DMSO were freshly distilled. Oxalyl chloride (2.09 ml_, 23.9 mmol) was 
dissolved in CH2CI2 (24 ml_) in a 3-necked flask and chilled to -60°C. Through 
an additional funnel, a solution of DMSO (3.70 ml_, 52.2 mmol) in CH2CI2 (14 
ml_) was carefully dripped to the flask to maintain the inside temperature at 
-60°C. The reaction mixture was then stirred for 15 minutes. A solution of allyl 
alcohol 141 (2000 mg, 10.9 mmol) in CH2CI2 (11 mL) was dropwise added to 
the flask through the additional funnel to maintain the inside temperature 
constantly at -60°C. The reaction mixture was stirred for 30 minutes. 
Triethylamine (7.6 mL, 54.3 mmol) was added to the flask. After 5 minutes, the 
chilling bath was removed to allow the reaction mixture to warm up gradually. 
Water was added to quench to reaction. The mixture was extracted multiply with 
CH2CI2. The organic phase was washed with water, dried and rotovaped. The 
residue was subjected to flash column chromatography to yield 143 (1030 mg, 
52%) as a clear oil. Rf (1 :3 ether/hexane) 0.56. 1 H NMR 8 6.36 (m, 1 H), 6.21 (d, 
J=18 Hz, 1H), 5.80 (d, J=11 Hz, 1H), 2.58 (t, J=7.5 Hz, 2H), 1.62 (m, 2H), 1.27 
(m, 12H), 0.88 (t, J=6 Hz, 3H); ™C NMR 8 200.9, 136.5, 127.6, 39.6, 31.8, 29.3 
(2C), 29.2 (2C), 23.9, 22.6, 14.0. HRMS for C12H22O M+H, calcd: 183.1749. 
Found: 183.1743. 

Preparatio n of 1 -Dodecen-3-one (143) bv Tsuii's allvl methvl carbonate 
method. 4 ^ A mixture of allylic alcohol 141 (1000 mg, 5.42 mmol), allyl methyl 
carbonate (1234 uL, 10.88 mmol), catalyst RuH2(PPh3)4 (62 mg, 0.054 mmol) 
and toluene (26 mL) was refluxed for 12 hours. Toluene was then rotovaped 



83 

away. The dark residue was chromatographed to afford 143 (833 mg, 83%) as 
a clear oil. Rf (1 :3 ether/hexane) 0.56. 

Preparation of 1 .6E-Dodecadien-3-one (144^ bv Swern oxidation. 4 8 Oxalyl 
chloride (2.11 ml_, 24.2 mmol) was dissolved in CH2CI2 (24 ml_) in a 3-necked 
flask and chilled to -60°C. A solution of DMSO (3.74 mL, 52.8 mmol) in CH2CI2 
(14 mL) was carefully dripped to the flask through an additional funnel, to 
maintain the inside temperature at -60°C. The reaction mixture was then stirred 
for 15 minutes. A solution of allyl alcohol 142 (2000 mg, 11.0 mmol) in CH2CI2 
(11 mL) was dropwise added to the flask through the additional funnel to 
maintain the inside temperature constant. The reaction mixture was stirred for 
30 minutes. Triethylamine (7.7 mL, 55.0 mmol) was added to the flask. After 5 
minutes, the chilling bath was removed to allow the reaction mixture to warm up 
gradually. Water was added to quench to reaction. The mixture was extracted 
multiply with CH2CI2. The organic phase was washed with water, dried and 
rotovaped. The residue was chromatographed to give 144 (1037 mg, 52%) as 
a clear oil. Rf (1 :3 ether/hexane) 0.47. 1 H NMR 8 6.36 (m, 1 H), 6.21 (d, J=1 7 Hz, 
1H), 5.82 (d, J=10 Hz, 1H), 5.43 (m, 2H), 2.65 (t, J=7 Hz, 2H), 2.31 (m, 2H), 1.96 
(m, 2H), 1.33-1.27 (m, 6H), 0.88 (t, J=6 Hz, 3H); ™C NMR 8200.2, 136.5, 131.6, 
128.2, 127.8, 39.5, 32.4, 31.3, 29.1, 26.9, 22.5, 14.0. HRMS for C12H20O, 
calcd: 180.1514. Found: 180.1513. Anal. Calcd for C12H20O: C, 79.94; H, 
11.18. Found: C, 79.70; H, 11.22. 

Preparation of 1 .6E-Dod ecadien-3-one (144^ bv Tsuii's allvl methvl carbonate 
method.49 a mixture of allylic alcohol 142 (1000 mg, 5.49 mmol), allyl methyl 
carbonate (1247 u.L, 10.98 mmol), catalyst RuH2(PPh3)4 (63 mg, 0.055 mmol) 
and toluene (28 mL) was refluxed for 12 hours. The mixture was rotovaped to 
remove toluene. The dark residue was chromatographed to afford 144 (683 
mg, 69%) as a clear oil. Rf (1 :3 ether/hexane) 0.47. 



84 



Preparation of 1-cyclopr opyldecan-1-one (135) bv Scheme 2-2 . NaH (60%, 57 
mg, 1.43 mmol) was placed in a Schlenk flask, washed with n-pentane (x3) and 
pumped. Trimethyloxosulfonium iodide (315 mg, 1.43 mmol) was added. DMSO 
(2 ml_) was dripped to the stirred solid mixture through a syringe. After hydrogen 
evolution, a milky solution turned clear and was stirred for 15 minutes. Ketone 
143 (200 mg, 1.10 mmol) in 1 ml_ DMSO was added. The mixture was stirred 
for 12 hours and quenched with water. The mixture was extracted with ether. 
The ether layer was dried, rotovaped, and chromatographed to give 135 (39 
mg, 18%) as an oil. Rf (1 :3 ether/hexane) 0.70. 1 H NMR 5 2.48 (t, J=7 Hz, 2H), 
1.87 (m, 1H), 1.55 (m, 2H), 1.21 (m, 12H), 0.94 (m, 2H), 0.82-0.77 (m, 5H); 13c 
NMR 5 211.1, 43.4, 31.8, 29.4 (2C), 29.2 (2C), 24.0, 22.6, 20.2, 14.0, 10.4 (2C). 
HRMS forCi3H240, calcd: 196.1827. Found: 196.1894. 
Preparation of 1-cyclopropyl-4E-decen-1-one (136) bv Scheme 2-2. NaH 
(60%, 130 mg, 3.25 mmol) was placed in a Schlenk flask, washed with n- 
pentane (x3) and pumped. Trimethyloxosulfonium iodide (715 mg, 3.25 mmol) 
was added. DMSO (11 ml_) was dripped to the stirred solid mixture through a 
syringe. After hydrogen evolution, a milky solution turned clear and was stirred 
for 15 minutes. Ketone 144 (450 mg, 2.50 mmol) in 1 ml_ DMSO was added. 
The mixture was stirred for 12 hours and quenched with water. The mixture was 
extracted with ether. The ether layer was dried, rotovaped and subjected to 
column chromatography to give 136 (115 mg, 24%) as a clear oil. Rf (1:3 
ether/hexane) 0.71. 1 H NMR 8 5.38 (m, 2H), 2.57 (t, J=7 Hz, 2H), 2.25 (q, J=7 
Hz, 2H), 1.95-1.85 (m, 3H), 1.34-1.24 (m, 6H), 0.97 (m, 2H), 0.87-0.79 (m, 5H); 
13 C NMR 5 210.3, 131.4, 128.3, 43.2, 32.4, 31.2, 29.1, 26.9, 22.4, 20.2, 13.9, 
10.4 (2C). HRMS forCi3H220 M+H, calcd: 195.1749. Found: 195.1764. 
1-Cvclopropvldecan-1-ol (145) . Magnesium turning (185 mg, 7.69 mmol) was 
finely ground in a dry mortar and placed in a 3-necked flask equipped with a 



85 



condenser, an additional funnel and a stirring bar. A bit of iodine crystal was 
added to the turning. Cyclopropyl bromide (308 |iL, 3.85 mmol) was dissolved 
in 4 ml_ THF and added into the additional funnel. About one third of the 
solution was dripped to the stirred turning. When the reaction started releasing 
heat and bubbles, the remaining cyclopropyl bromide solution was added 
dropwise. The mixture was heated in 65°C oil bath for 20 minutes. At room 
temperature, aldehyde 139 (200 mg, 1.28 mmol) was added. The mixture was 
stirred for 1 hour and quenched with NH4CI (aq.). The mixture was extracted 
with ether. The ether layer was dried, rotovaped and chromatographed to yield 

145 (193 mg, 76%) as an oil. Rf (1:1 ether/hexane) 0.59. 1 H NMR 5 2.78 (m, 
1H), 1.93 (s, 1H), 1.51 (m, 2H), 1.41-1.20 (m, 15H), 0.81 (t, J=7 Hz, 3H), 0.42 (m, 
2H), 0.16 (m, 2H); 1 3C NMR 8 76.7, 37.2, 31.8, 29.7, 29.5 (2C), 29.2, 25.7, 22.6, 
17.8, 14.0,2.6, 2.3. HRMS forCi3H260, calcd: 198.1984. Found: 198.1880. 
1-Cvclopropvl-4E-decen-1-ol (146V Magnesium turning (187 mg, 7.79 mmol) 
was finely ground in a dry mortar and placed in a 3-necked flask equipped with 
a condenser, an additional funnel and a stirring bar. A bit of iodine crystal was 
added to the turning. Cyclopropyl bromide (312 ul, 3.90 mmol) was dissolved 
in 4 mL THF and added into the additional funnel. About one third of the 
solution was dripped to the stirred turning. When the reaction started releasing 
heat and bubbles, the remaining cyclopropyl bromide solution was added 
dropwise. The mixture was heated in 65°C oil bath for 20 minutes. At room 
temperature, aldehyde 140 (200 mg, 1.30 mmol) was added. The mixture was 
stirred for 1 hour and quenched with NH4CI (aq.). The mixture was extracted 
with ether. The ether layer was dried, rotovaped and chromatographed to afford 

146 (178 mg, 70%) as an oil. Rf (1:1 ether/hexane) 0.58. 1 H NMR 8 5.36 (m, 
2H), 2.81 (m, 1H), 2.07 (m, 2H), 1.91 (m, 3H), 1.60 (m, 2H), 1.22 (m, 6H), 0.82 
(m, 4H), 0.43 (m, 2H), 0.18 (m, 2H); 13 C NMR 8 130.8, 129.7, 76.2, 37.0, 32.5, 



86 



31.3, 29.2, 28.8, 22.4, 17.8, 14.0, 2.6, 2.4. HRMS for C13H24O, calcd: 
196.1827. Found: 196.1819. 

Preparation of 1-cyclopropyldecan-1-one (135) by Scheme 2-4 . Alcohol 136 
(274 mg, 1.38 mmol) was dissolved in CH2CI2 (3 mL). To this solution was 
added finely ground mixture of PCC (598 mg, 2.77 mmol) and silica gel (600 
mg). The oxidation was complete in 4 hours and diluted with a large amount of 
ether. The ether solution was forced through a celite bed and the bed was 
rinsed with ether. The ether solution was rotovaped and chromatographed to 
yield 135 (224 mg, 83%) as an oil. Rf (1 :3 ether/hexane) 0.70. 
Preparation of 1-cvclo propvl-4E-decen-1-one (136) bv Scheme 2-4 . Alcohol 
146 (150 mg, 0.765 mmol) was dissolved in CH2CI2 (1.5 mL). To this solution 
was added finely ground mixture of PCC (330 mg, 1.53 mmol) and silica gel 
(330 mg). The oxidation was complete in 4 hours and diluted with a large 
amount of ether. The ether solution was forced through a celite bed and the bed 
was rinsed with ether. The ether solution was rotovaped and chromatographed 
to give 136 (116 mg, 78%) as an oil. Rf (1 :3 ether/hexane) 0.71. 
Phenvlftrans-2-phenylcvclopropvnmethanone (1 38) . NaH (60%, 231 mg, 5.77 
mmol) was placed in a 3-necked flask, washed with n-pentane (x3) and fully 
pumped. Trimethyloxosulfonium iodide (1270 mg, 5.77 mmol) was added. 
DMSO (10 mL) was dripped to the solid mixture through an additional funnel. 
After hydrogen evolution, a milky solution turned clear and was stirred for 15 
minutes. Trans-chalcone 147 (1000 mg, 4.81 mmol) was added. The mixture 
was stirred for 20 hours and quenched with water. The mixture was extracted 
with ether. The ether layer was dried, rotovaped, and chromatographed to give 
138 (1080 mg, 100%) as a white solid. Rf (1:3 ether/hexane) 0.48. 1 H NMR 6 
8.01-7.98 (m, 2H), 7.59-7.56 (m, 1H), 7.49-7.43 (m, 2H), 7.35-7.29 (m, 2H), 7.25- 
7.22 (m, 1H), 7.21-7.17 (m, 2H), 2.91 (m, 1H), 2.70 (m, 1H), 1.93 (m, 1H), 1.56 



87 



(m, 1H); 1 3c NMR 8 198.5, 140.5, 137.8, 132.9, 128.5 (4C), 128.1 (2C), 126.6 
(2C), 126.2, 30.0, 29.3, 19.2. HRMS for C16H14O, calcd: 222.1045. Found: 
222.1056. 

Tridecan-4-one (148) . A mixture of cyclopropyl ketone 135 (200 mg, 1.02 
mmol), TBTH (549 ul, 2.04 mmol) and AIBN (84 mg, 0.51 mmol) in benzene (3 
ml_) was degassed by argon stream for 15 minutes. The mixture was refluxed at 
80°C for 18 hours. A DBU workup procedure was used to remove excess TBTH 
and other tin byproducts.34d,93 reaction mixture was diluted with ether. 
Following addition of DBU (335 u.L, 2.24 mmol) and 2-3 drops of water, an 
ethereal solution of iodine was added dropwise until the iodine orange color 
persisted. Rapid suction filtration through silica gel bed was performed. The 
silica gel bed was rinsed with ether, and the solution was concentrated and 
subjected to flash column chromatography to afford 148 (162 mg, 80%) as an 
oil. Rf (1:3 ether/hexane) 0.47. 1|H NMR 2.35 (m, 4H), 1.62-1.53 (m, 4H), 1.40- 
1.23 (m, 12H), 0.92-0.85 (m, 6H), identical to that published in Sadtler NMR 
Spectra (#23462) ;94 13q NMR 5 211.6, 44.7, 42.8, 31.9, 29.4 (2C), 29.3 (2C), 
23.9, 22.7, 17.3, 14.1, 13.8, identical to that published in Sadtler 1 3c NMR 
Spectra (#5994)95 HRMS forCi3H260, calcd: 198.1984. Found: 198.1987. 
7E-Tridecen-4-one (149) . A mixture of cyclopropyl ketone 136 (100 mg, 0.515 
mmol), TBTH (277 uJ_, 1.03 mmol) and AIBN (42 mg, 0.258 mmol) in benzene (2 
ml_) was degassed by argon stream for 15 minutes. The mixture was refluxed at 
80°C for 18 hours. The reaction mixture was rotovaped and subjected to flash 
column chromatography to give 149 (81 mg, 80%) as an oil. Rf (1:3 
ether/hexane) 0.63. 1H NMR 5 5.33 (m, 2H), 2.40-2.28 (m, 4H), 2.24-2.15 (m, 
2H), 1.88 (m, 2H), 1.52 (m, 2H), 1.28-1.20 (m, 6H), 0.86-0.78 (m, 6H); 13c NMR 
8 210.8, 131.5, 128.3, 44.8, 42.6, 32.4, 31.3, 29.1, 26.8, 22.5, 17.2, 14.0, 13.7. 
HRMS forCi3H240, calcd: 196.1827. Found: 196.1808. 



88 



1-(4-Methoxyphenyl)-1-butanone (150) . A mixture of cyclopropyl ketone 137 
(200 mg, 1.14 mmol), TBTH (458 uL, 1.70 mmol) and AIBN (56 mg, 0.341 mmol) 
in benzene (2.5 ml_) was degassed by argon stream for 15 minutes. The mixture 
was refluxed at 80°C for 2 hours. The reaction mixture was rotovaped and 
chromatographed to afford 150 (186 mg, 92%) as a solid. Rf (1 :1 ether/hexane) 
0.71 . 1 H NMR 8 7.85 (d, J=9 Hz, 2H), 6.83 (d, J=9 Hz, 2H), 3.76 (s, 3H), 2.80 (t, 
J=7 Hz, 2H), 1.66 (m, 2H), 0.91 (t, J=7 Hz, 3H); 1 3c NMR 5 198.7, 163.1, 130.0 
(3C), 113.4 (2C), 55.2, 39.9, 17.8, 13.7. HRMS forCnH-|402, calcd: 178.0994. 
Found: 178.0993. 

1 .4-Diphenvlbutan-1-one (151^ . A mixture of compound 138 (200 mg, 0.901 
mmol), TBTH (727 ul, 2.70 mmol) and AIBN (148 mg, 0.901 mmol) in benzene 
(4.5 ml_) was degassed by argon stream for 15 minutes. The mixture was 
refluxed at 80°C for 5 hours. Quenched with ethanol, the reaction mixture was 
rotovaped and chromatographed to afford 151 (173 mg, 86%) as a clear liquid 
which slowly solidified. Rf (1 :3 ether/hexane) 0.42. 1 H NMR 5 7.90-7.87 (m, 2H), 
7.52-7.46 (m, 1H), 7.41-7.36 (m, 2H), 7.29-7.23 (m, 2H), 7.19-7.14 (m, 3H), 2.92 
(t, J=7 Hz, 2H), 2.69 (t, J=7 Hz, 2H), 2.05 (m, 2H); 13c NMR 8 199.8, 141.5, 
136.9, 132.7, 128.4 (2C), 128.3 (2C), 128.2 (2C), 127.8 (2C), 125.8, 37.5, 35.0, 
25.5. HRMS forC-|6Hi60, calcd: 224.1201 . Found: 224.1225. 
3-Methoxvcarbonvl-2- cvclohexen-1-one(1 59^ .52 This synthetic work was 
identical to that described by Lange and Otulakowski. 52 A 3-necked flask 
equipped with an additional funnel, a condenser and a thermometer was used. 
Cyclohexanecarboxylic acid 156 (25.0 g, 195 mmol) was placed in the flask. 
Freshly distilled thionyl chloride (17.4 ml_, 238 mmol) was dropwise added 
through the additional funnel in 30 minutes. This mixture was refluxed for 2 
hours. Red phosphorus (310 mg, 10.0 mmol) was added with stirring. The 
temperature was increased to 90°C and bromine (12.3 ml_, 238 mmol) was 



89 



dropwise added in 1.5 hour as the temperature was maintained below 105°C. 
The mixture was heated at 100°C for an additional hour and then chilled to 5°C. 
Anhydrous methanol (40 mL, 989 mmol) was dropwise added. The mixture was 
refluxed for 15 minutes, cooled, and poured into ice-cold water. The mixture 
was extracted with ether. The organic phase was washed with 1 M Na2S203 
and saturated NaHC03 aqueous solutions, dried and rotovaped. The residue 
was distilled to give ester 157 (38.4 g, 89%). A solution of ester 157 (20.0 g, 
90.5 mmol) and distilled quinoline (17.1 mL, 145 mmol) was refluxed for 1 hour. 
The mixture was cooled to room temperature, treated with 20% HCI (100 mL) 
and extracted with ether. The organic extract was washed with 10% HCI, water 
and saturated NaHC03 (aq.). This extract was dried, rotovaped and 
chromatographed to give 158 (12.6 g, 99%). Compound 158 (5.00 g, 35.8 
mmol) was dissolved in benzene (50 mL) and stirred. To this solution was 
dropwise added a mixture of Cr03 (10.0 g, 100 mmol) in acetic anhydride (25 
mL) and glacial acetic acid (50 mL) over 30 minutes. After stirring for additional 
20 minutes, benzene (50 mL) was added to dilute the reaction mixture. Chilled 
by ice, this acidic mixture was slowly neutralized with saturated KOH aqueous 
solution. The mixture was extracted with ether. The extract was washed with 
water, dried, rotovaped and chromatographed to afford 159 (2.81 g, 52%) as a 
clear oil. Rf (2:1 ether/hexane) 0.48. 1 H NMR 8 6.73 (t, J=2 Hz, 1 H), 3.84 (s, 3H), 
2.60 (dt, J=6 Hz, 2 Hz, 2H), 2.46 (m, 2H), 2.07 (m, 2H); ™C NMR 5 199.6, 166.8, 
148.6, 132.9, 52.4, 37.5, 24.7, 22.0. HRMS for C8H10O3, calcd: 154.0630. 
Found: 154.0650. 

6-Methoxvcarbonvlbicvclof4.1 .OIheptan-2-one (153) . NaH (60%, 57 mg, 1.43 
mmol) was placed in a 3-necked flask, washed with n-pentane (x3) and 
pumped to dry. Trimethyloxosulfonium iodide (315 mg, 1.43 mmol) was added. 
DMSO (2 mL) was dripped to the solid mixture through an additional funnel. 



90 



After hydrogen evolution, a milky solution turned clear and was stirred for 15 
minutes. Compound 159 (200 mg, 1.30 mmol) in DMSO (1 ml_) was added. 
The mixture was stirred overnight and quenched with water. The mixture was 
extracted with ether and the ether layer was dried, rotovaped, and 
chromatographed to give 153 as an oil (76 mg, 35%). Rf(2:1 ether/hexane) 
0.37. 1 H NMR 8 3.71 (s, 3H), 2.39-2.17 (m, 4H), 2.13-2.01 (m, 1H), 1.87-1.79 
(m, 1H), 1.72-1.67 (m, 1H), 1.64-1.54 (m, 2H); 13 C NMR 8 205.3 (s), 173.0 (s), 
52.1 (q), 36.4 (t), 33.6 (d), 28.7 (s), 22.3 (t), 18.0 (t), 16.7 (t). HRMS for C9H12O3 
M+H, calcd: 169.0865. Found: 169.0849. 

5.5-Diphenvlbicvclo[4.1 .0]heptan-2-one (154) . NaH (60%, 39 mg, 0.968 mmol) 
was placed in a 3-necked flask, washed with n-pentane (x3) and pumped to dry. 
Trimethyloxosulfonium iodide (213 mg, 0.968 mmol) was added. DMSO (2 ml_) 
was dripped to the solid mixture through an additional funnel. After hydrogen 
evolution, a milky solution turned clear and was stirred for 15 minutes. 4,4- 
Diphenyl-2-cyclohexen-1-one 160 (200 mg, 0.806 mmol) was added and the 
mixture was stirred overnight. The reaction was quenched with water and 
extracted with ether. The ether layer was dried, rotovaped and 
chromatographed to give 154 as a white solid (171 mg, 81%). Rf (ether) 0.65. 
IR (KBr) 1 681 ; 1 H NMR 8 7.38-7.1 7 (m, 1 0H), 2.55-2.42 (m, 1 H), 2.33-2.1 1 (m, 
4H), 1.89-1.76 (m, 1H), 1.41-1.35 (m, 1H), 1.21-1.13 (m, 1H); ™C NMR 8 207.3 
(s), 148.3 (s), 146.3 (s), 128.3 (d), 128.2 (d), 127.7 (d), 126.7 (d), 126.4 (d), 
126.2 (d), 44.5 (s), 33.5 (t), 28.5 (d), 27.9 (t), 27.6 (d), 10.0 (t). HRMS for 
C19H18O M+H, calcd: 263.1436. Found: 263.1441. 

Tricyclic ketone 155. NaH (60%, 320 mg, 8.00 mmol) was placed in a 3-necked 
flask, washed with n-pentane (x3) and pumped to dry. Trimethyloxosulfonium 
iodide (1760 mg, 8.00 mmol) was added. DMSO (10 mL) was dripped to the 
solid mixture through an additional funnel. After hydrogen evolution, a milky 



91 



solution turned clear and was stirred for 15 minutes. (-)-Verbenone 161 (1000 
mg, 6.67 mmol) in DMSO (5 ml_) was added. This mixture was stirred for 24 
hours. The reaction was quenched with water and extracted with ether. The 
ether layer was dried, rotovaped and chromatographed to give 155 (1 187 mg, 
100%) as a clear oil. Rf (1 :2 ether/hexane) 0.49; Rf (1 :1 ether/hexane) 0.58. 1 H 
NMR 5 2.26-2.21 (m, 1H), 2.19-2.14 (m, 2H), 1.61 (m, 1H), 1.48 (m, 1H), 1.32 (d, 
J=1.2 Hz, 3H), 1.30 (m, 1H), 1.17 (d, J=1.2 Hz, 3H), 1.01 (d, J=0.9 Hz, 3H), 0.77 
(m, 1H); 1 3c NMR 8 209.5, 57.8, 49.5, 45.4, 30.5, 26.0, 22.7, 22.0, 21.8, 21.7, 
21.5. HRMS forCnHi60 M+H, calcd: 165.1279. Found: 165.1300. 
4-Methoxycarbonvlcvc loheptanone (1 65) . A mixture of 153 (40 mg, 0.238 
mmol), TBTH (192 u.L, 0.714 mmol) and AIBN (40 mg, 0.238 mmol) in benzene 
(2.5 ml_) was degassed by argon stream for 15 minutes. The mixture was 
refluxed at 80°C for 2 hours. Quenched with ethanol, the reaction mixture was 
rotovaped and chromatographed to give 165 as an oil (28 mg, 69%). Rf (2:1 
ether/hexane) 0.38. IR (KBr) 1734, 1700; 1 H NMR 8 3.70 (s, 3H), 2.66-2.46 (m, 
4H), 2.18-2.04 (m, 2H), 2.02-1.76 (m, 3H), 1.73-1.59 (m, 2H); 1 3c NMR 8 213.4 
(s), 175.4 (s), 51.7 (q), 46.3 (d), 43.4 (t), 41.5 (t), 32.5 (t), 26.3 (t), 22.4 (t). These 
NMR spectra were identical to those reported by Cossy.55 
3-Methvl-4.4-diphenvlc vclohexanone (1 66) . A mixture of 154 (84 mg, 0.321 
mmol), TBTH (173 u.L, 0.642 mmol) and AIBN (53 mg, 0.321 mmol) in benzene 
(3.2 ml_) was degassed by argon stream for 15 minutes. The mixture was 
refluxed at 80°C for 2.5 hours. Quenched with ethanol, the reaction mixture was 
rotovaped and chromatographed to give 166 as a white solid (73 mg, 86%). Rf 
(ether) 0.71. 1h NMR 8 7.55-7.08 (m, 10H), 3.37-3.32 (m, 1H), 2.98-2.86 (m, 
2H), 2.70 (m, 1H), 2.41-2.38 (m, 1H), 2.36-2.25 (m, 2H), 0.81 (d, J=7 Hz, 3H); 
1 3c NMR 8 210.9 (s), 146.8 (s), 145.0 (s), 128.9 (d), 128.3 (d), 126.8 (d), 126.5 
(d), 126.2 (d), 125.7 (d), 48.2 (s), 45.7 (t), 38.4 (t), 37.7 (d), 29.6 (t), 16.7 (q). 



92 



Anal. Calcd for Ci 9H20O: C, 86.31 ; H, 7.63. Found: C, 86.27; H, 7.85. HRMS 
forCi9H20O M+H, calcd: 265.1592. Found: 265.1598. 

Bicyclic ketone 167 . A mixture of ketone 155 (200 mg, 1.22 mmol), TBTH (656 
U.L, 2.44 mmol) and AIBN (80 mg, 0.49 mmol) in benzene (4 ml_) was degassed 
by argon stream for 15 minutes. The mixture was refluxed at 80°C overnight. 
Quenched with ethanol, the reaction mixture was rotovaped and 
chromatographed to give 167 as a clear oil (86 mg, 76%). Rf (1 :1 ether/hexane) 
0.66. 1 H NMR 8 2.54 (m, 2H), 2.37 (d, J=2 Hz, 2H), 1 .88 (t, J=6 Hz, 1 H), 1 .64 (d, 
J=10 Hz, 1H), 1.36 (s, 3H), 1.19 (s, 3H), 1.09 (s, 3H), 1.02 (s, 3H); 1 3c NMR 8 
214.5, 58.1, 53.6, 48.2, 41.1, 32.0, 31.8, 29.0, 27.2, 25.7, 25.4. HRMS for 
C11H18O, calcd: 166.1358. Found: 166.1366. 

(Ethoxvcarbonvlmethvntriphenvlphosphonium bromide M83) . In an Erlenmeyer 
flask, triphenylphosphine (131 g, 0.5 mol) was dissolved in benzene (250 ml_). 
This solution was stirred vigorously while ethyl bromoacetate (83.5 g, 0.5 mol) 
was added dropwise. A white precipitate formed immediately. After 3 hours the 
white precipitate was collected by a Buchner funnel and washed with cold 
benzene (250 ml_) and cold pentane (200 ml_). The white solid then was 
pumped overnight to dry. Compound 183 (213 g, 99.3% yield) was thus 
obtained. 1 H NMR 8 7.91-7.70 (m, 12H), 7.50-7.35 (m, 3H), 5.49 (m, 2H), 4.03 
(m, 2H), 1.06 (m, 3H); 1 3c NMR 8 164.4, 135.1 (3C), 133.9 (3C), 133.8 (3C), 
130.3 (3C), 130.1 (3C), 128.2 (3C), 117.824 (j3ip.i3C=89 Hz for this doublet), 
62.8, 33.1 (J31P-13C=57 Hz for this doublet), 13.6. HRMS for C22H22O2P, 
calcd: 349.1357. Found: 349.1358. 

Ethvl allenecarboxvla te M80h 66 This synthetic work was identical to that 
described by Lang and Hansen. 66 In a 3-necked flask, Wittig salt 183 (30 g, 70 
mmol) was dissolved in CH2CI2 (280 ml_) at room temperature. To this flask a 
solution of freshly distilled triethylamine (19.7 mL, 140 mmol) in CH2CI2 (70 



93 



ml_) was added in 5 minutes with an additional funnel. Then the solution of 
freshly distilled acetyl chloride (5.0 ml_, 70 mmol) in 70 ml_ CH2CI2 was added 
in 15 minutes. The reaction was monitored with TLC (stained in KMn04-NaOH 
aqueous solution). The reaction was completed in 1 hour. The reaction mixture 
was rotovaped to remove CH2CI2. To the semi-solid residue was added 400 
ml_ pentane. The slurry was then stirred for 2 hours. The precipitate was 
removed by a Buchner funnel and the pentane filtrate was rotovaped to 50 ml_ 
in volume. The precipitate was then again filtered with a Buchner funnel. 
Distillation of the filtrate under reduced pressure afforded 180 (470 mg, 17%) 
as colorless liquid, boiling point 82°C at 9.5 torr. Rf (1 :1 hexane/ ether) 0.66. 1 H 
NMR 5 5.64 (t, 1H), 5.22 (d, 2H), 4.21 (q, 2H), 1.29 (t, 3H); 1 3c NMR 5 215.6, 
165.7, 88.0, 79.2, 60.9, 14.1. 

2-Trimethylsilvloxv-1 . 3-cyclohexadiene (185^ .68 This synthetic work was 
identical to that described by Rubottom and Grube. 68 THF (240 ml_) was placed 
in a flask and chilled to -78°C. To this flask was added diisopropylamine (13.6 
g, 0.135 mol) and n-butyl lithium (2.5M in hexane, 58.8 ml_, 0.147 mol). After 30 
minutes, 2-cyclohexen-1-one 178 (12.0 g, 0.122 mol) was dropwise syringed 
into the reaction flask over 5 minutes. After stirring at -78°C for 20 minutes, 
trimethylsilyl chloride (26.6 g, 0.245 mol) was added. The reaction mixture was 
allowed to warm up to room temperature and stirred for 2 hours before it was 
poured into an ice-cold stirred mixture of n-pentane (500 ml_) and saturated 
NaHC03 aqueous solution (300 mL). After 10 minutes, the pentane phase was 
quickly separated, dried with MgS04, and rotovaped. Vacuum distillation of the 
residue afforded 185 (18.0 g, 87%) as a clear liquid, boiling point 100°C at 7.5 
torr. IR (KBr) 3422, 1649, 1252, 1199. *H NMR 8 5.96 (m, 1H), 5.79 (m, 1H), 
4.98 (m, 1H), 2.28-2.17 (m, 4H), 0.29 (s, 9H); 13 C NMR 5 148.1, 128.8, 126.5, 
102.4, 22.6, 21.8, 0.2. 



94 



3.4-Dimethoxvcarbonvlphenol (189) . 2-Trimethylsilyloxy-1 ,3-cyclohexadiene 
185 (1000 mg, 5.88 mmol) and dimethyl acetylenedicarboxylate 186 (1250 
mg, 8.82 mmol) were refluxed in 5 ml_ toluene at 120°C for 1 day. Then to the 
mixture was added 3 M HCI (5 ml_). After stirring for 3 hours, the mixture was 
separated and the aqueous phase was multiply extracted with ethyl acetate. 
The organic layer was dried over MgS04 and rotovaped. Chromatographic 
purification of the residue gave 189 (1100 mg, 89%) as a white crystal. Rf (1:2 
hexane/ether) 0.17; IR (KBr) 3410 (broad), 1638 (broad); 1 H NMR 5 7.74 (d, 
J=8.4 Hz, 1H), 7.01 (d, J=2.4 Hz, 1H), 6.92 (dd, J=8.4 Hz, 2.4 Hz, 1H), 3.91 (s, 
3H), 3.87 (s, 3H); 1 3c NMR 5 169.6, 167.2, 159.3, 135.6, 131.9, 121.5, 117.3, 
115.3, 53.0, 52.5. Anal. Calcd for C10H10O5: C, 57.13; H, 4.80. Found: C, 
57.15; H, 4.80. 

Ethvl 4-hydroxybenzoate (191) . In a flask 185 (200 mg, 1.18 mmol) and ethyl 
propiolate 190 (138 mg, 1.41 mmol) was refluxed in 1 ml_ toluene for 16 hours. 
The reaction was monitored with GC. To workup to the mixture was added 1N 
HCI and stirred for 4 hours. The mixture then was multiply extracted with ether. 
The ether phase was dried, rotovaped and chromatographed to give 191 (185 
mg, 95%) as a white crystal. Melting point: 116-118°C. Rf (1:1 hexane/ether) 
0.43. 1 H NMR 5 7.96 (m, 2H), 6.89 (m, 2H), 4.36 (q, J=7 Hz, 2H), 1 .39 (t, J=7 Hz, 
3H); 1 3c NMR 5 167.4, 160.7, 131.9, 122.3, 115.3, 61.1, 14.2. Anal. Calcd for 
C9H10O3: C, 65.04; H, 6.07. Found: C, 64.95; H, 6.08. 

2.3-Dimethoxvcarbonylbi cvclor2.2.21oct-2-en-5-one (1 77) . Diene 185 (10.7 g, 
59.2 mmol) and dimethyl acetylenedicarboxylate 186 (10.1 g, 71.1 mmol) were 
refluxed in benzene (200 ml_) at 80°C overnight. After benzene was rotovaped, 
to the residue was added ether (200 ml_) and 6M HCI (20 ml_). After stirring for 8 
hours, the ether phase was separated. The aqueous layer was extracted with 
ether and ethyl acetate. The organic extracts were combined, dried and 



95 



rotovaped. Chromatographic purification of the residue afforded 177 (9.3 g, 
61%) as a yellow thick oil. Rf (1:2 hexane/ether) 0.30. Rl (KBr) 2954, 1723, 
1 636; 1 H NMR 8 3.72 (s, 3H), 3.70 (s, 3H), 3.63 (m, 1 H), 3.43 (m, 1 H), 1 .68-1 .88 
(m, 4H); 1 3C NMR 8 208.6, 166.0, 164.7, 143.4, 134.6, 52.4, 49.6, 38.8, 34.9, 
24.0, 22.7. Anal. Calcd for C12H14O5: C, 60.50; H, 5.92. Found: C, 60.37; H, 
6.08. 

2-Ethoxvcarbonvlbicyclo[2.2.21oct-2-en-5-one (176) . In a flask 185 (15.0 g, 
88.2 mmol), ethyl propiolate 190 (13.0 g, 132 mmol) and a few BHT (i.e. 2,6-di- 
t-butyl-4-methylphenol) crystals were refluxed in benzene (44 ml_) at 70-75°C 
for 7 days. Then the reaction mixture was rotovaped to remove benzene and 
acidified by 1M HCI. After stirring overnight, the aqueous mixture was extracted 
with chloroform. The chloroform phase was dried, rotovaped and 
chromatographed to give 176 (15.1 g, 88%) as a colorless oil. Rf (ether) 0.67. 
1 H NMR 8 7.20 (dd, J=7 Hz, 2 Hz, 1H), 4.24 (q, J=7 Hz, 2H), 3.62 (m, 1H), 3.35 
(m, 1H),2.07 (m,2H), 1.84-1.56 (m,4H), 1.33 (t, J=7 Hz, 3H); 13c NMR 8 210.5, 
164.0, 140.0, 138.0, 60.6, 49.6, 39.5, 31.9, 24.1, 22.5, 14.1. Anal. Calcd for 
C11H14O3: C, 68.02; H, 7.27. Found: C, 67.83; H, 7.40. 

1 .2-Dimethoxvcarbonylt ricvclor3.3.0.0^a]octan-3-one (174^ . Octenone 177 
(180 mg, 0.76 mmol) was dissolved in acetone (9.6 ml_) in a Pyrex tube. The 
solution was degassed with dry nitrogen stream for 30 minutes and then stirred 
under direct irradiation of a 450W Hanovia lamp for 24 hours. The reaction 
mixture was rotovaped and chromatographed to give 174 (150 mg, 83%) as a 
clear thick oil. Rf (2:1 ether/hexane) 0.37. IR (KBr) 2955, 1720 (broad), 1637 
(weak); 1H NMR 8 3.75 (s, 3H), 3.72 (s, 3H), 3.46 (m, 1H), 3.14 (d, J=6 Hz, 1H), 
2.74 (m, 1H), 2.25 (m, 2H), 1.96 (d, J=18 Hz, 1H), 1.65 (m, 2H); 13q NMR 8 
207.0 (s) 169.5 (s), 165.2 (s), 57.3 (s), 56.1 (s), 52.7 (q), 52.3 (q), 47.5 (t), 41.8 



96 



(d), 39.8 (t), 38.6 (d), 24.7 (t). Anal. Calcd for C12HI4O5: C, 60.50; H, 5.92. 
Found: C, 60.43, H, 6.08. 

Preparation of 174 using acetophenone as the triplet sensitizer and solvent . 
Octenone 177 (400 mg, 1.67 mmol) was dissolved in acetophenone (20 ml_) in 
a Pyrex tube. The solution was degassed with dry nitrogen stream for 30 
minutes and then stirred under direct irradiation of a 450W Hanovia lamp for 12 
hours. The reaction mixture was distilled at 1.5 torr to remove acetophenone 
(boiling point 83-86°C at 1.5 torr). The residue was chromatographed to give 
174 (364 mg, 92%) as a clear thick oil. Rf (2:1 ether/hexane) 0.37. 

1 -Ethoxvcarbonvltricvclo[3.3.0.Q 2^8 ]octan-3-one (173) . Octenone 176 (316 mg, 
1 .61 mmol) was dissolved in acetone (20 ml_) in a Pyrex tube. The solution was 
degassed with dry nitrogen stream for 30 minutes and stirred under irradiation 
of a 450W Hanovia lamp for 24 hours. The reaction mixture then was rotovaped 
and chromatographed to produce 173 as a colorless oil (265 mg, 84%). This 
reaction was repeated with the solution of octenone 176 (15.1 g, 77.8 mmol) in 
acetone (970 ml_) irradiated for 48 hours. The yield for 173 was increased to 
88% (13.3 g). Rf (ether) 0.67. IR (KBr) 2957, 1724, 1624 (weak); 1 H NMR 8 4.17 
(q, J=7 Hz, 2H), 3.42 (m, 1H), 2.71-2.58 (m, 3H), 2.23 (m, 2H), 1.83 (d, J=18 Hz, 
1 H), 1 .65 (m, 2H), 1 .27 (t, J=7 Hz, 3H); 1 3q NMR 8 211.7 (s), 1 71 .3 (s), 60.7 (t), 
49.8 (s), 47.6 (d), 46.9 (t), 40.6 (t), 38.9 (d), 37.8 (d), 24.6 (t), 14.1 (q). Anal. 
Calcd for C1 1 Hi 4O3: C, 68.02; H, 7.27. Found: C, 67.88; H, 7.36. 
1-rerf-Butvldiphenvlsilo xvmethvltricvclor3.3.0.o 2 ^loctan-3-ol (199V In a flask, 
tricyclic ketoester 173 (560 mg, 2.86 mmol) was dissolved in CH2CI2 (7.2 ml_) 
and chilled at -78°C. To this flask was dropwise added DIBAH (1 .0 M solution in 
hexane, 14.3 ml_, 14.3 mmol) by a syringe. The mixture was stirred at -78°C for 

2 hours and then warmed up to room temperature. When the reaction was 
complete, it was quenched with methanol at -78°C. To this mixture was added 



97 



saturated sodium potassium tartrate (Rochelle's salt) aqueous solution and 
stirred overnight to clear up the aqueous layer. The mixture then was extracted 
with ethyl acetate. The acetate extract was dried and rotovaped to afford diol 
198 (440 mg, 99%). Rf (ethyl acetate) 0.28. Without further purification diol 198 
(420 mg, 2.73 mmol) was dissolved in pyridine (5.4 mL). At 0°C to this solution 
was added fe/f-butyldiphenylsilyl chloride (851 mL, 3.27 mmol). The mixture 
was stirred for 10 hours and quenched with water. The mixture then was 
rotovaped and pumped to remove pyridine. The residue was chromatographed 
to give 199 (393 mg, 37%) as a clear thick oil. Rf (1:2 hexane/ether) 0.53. 1 H 
NMR 5 7.71 -7.65 (m, 4H), 7.39-7.32 (m, 6H), 4.78 (m, 1 H), 3.79 (dd, J=27 Hz, 1 1 
Hz, 2H), 2.64 (m, 1H), 2.51 (m, 1H), 2.31-1.79 (m, 4H), 1.57-1.45 (m, 1H), 1.38 
(m, 1H), 1.27 (m, 1H), 1.06 (s, 9H); 1 3c NMR 8 135.5 (d), 134.0 (s), 129.5 (d), 
127.5 (d), 76.1 (d) and 73.0 (d), 65.9 (t) and 65.8 (t), 50.5 (s) and 49.2 (s), 46.7 
(t), 45.1 (d) and 43.7 (d), 39.8 (t) and 39.7 (t), 38.6 (d) and 38.2 (d), 32.1 (d) and 
29.1 (d), 26.9 (q) and 26.8 (q), 24.9 (t) and 23.6 (t), 19.2 (s). HRMS for 
C25H3202Si, calcd: 392.2172. Found: 392.2053. 

1-rerf-Butvldiphenvlsiloxvmethvltricvclo[3.3.0.Q 2 ^1octan-3-one (172) . PCC 
(420 mg, 1.94 mmol) was finely ground with Kieselgel silica gel 60 (420 mg, 1 
weight equivalent) and the light orange powder was suspended in CH2CI2 (4 
mL). Tricyclic alcohol 199 (320 mg, 0.816 mmol) was dissolved in CH2CI2 (2 
mL) and added to the PCC suspension. After 2 hours the reaction mixture was 
filtered through a celite bed in a Buchner funnel. The brown cake was washed 
with copious amount of ether. The filtrate was rotovaped and chromatographed 
to yield 172 (222 mg, 70%) as a clear thick oil. Rf (1 :1 hexane/ether) 0.46. 1 H 
NMR 8 7.67-7.63 (m, 4H), 7.42-7.37 (m, 6H), 3.92 (dd, J=31 Hz, 1 1 Hz, 2H), 2.87 
(m, 1H), 2.58 (m, 1H), 2.07 (m, 2H), 1.86 (m, 1H), 1.75 (d, J=18 Hz, 1H), 1.63- 
1 .51 (m, 2H), 1 .27 (m, 1 H), 1 .06 (s, 9H); 1 3 C NMR 8 21 4.8 (s), 1 35.4 (d), 1 33.5 



98 



(s), 129.7 (d), 127.6 (d), 64.3 (t), 51.9 (s), 47.2 (t), 43.2 (d), 39.9 (t), 39.5 (d), 34.4 
(d), 26.8 (q), 25.3 (t), 19.2 (s). HRMS for C25H30O2Si M+H, calcd: 391.2093. 
Found: 391.2040. Anal. Calcd for C25H3o02Si: C, 76.88; H, 7.74. Found: C, 
76.73; H, 7.84. 

1-Terf-Butyldiphenvlsiloxvmethylbicyclo[3.3.0]octan-3-one (202) . To a solution 
of tricyclic ketone 172 (120 mg, 0.308 mmol) in benzene (3.1 ml_) was added 
TBTH (250 ml_, 0.923 mmol) and AIBN (50 mg, 0.308 mmol). The mixture was 
degassed with argon for 15 minutes and refluxed at 80°C for 4 hours. The 
reaction mixture was rotovaped and chromatographed to give 202 (89 mg, 
83%) as a clear oil along with unreacted starting ketone 172 (13 mg). Rf (1:1 
hexane/ether) 0.54. 1h NMR 8 7.66-7.63 (m, 4H), 7.43-7.38 (m, 6H), 3.52 (m, 
2H), 2.64 (m, 1 H), 2.59-2.52 (m, 2H), 2.1 1 (m, 2H), 1 .95 (m, 1 H), 1 .75-1 .49 (m, 
4H), 1.39 (m, 1H), 1.05 (s, 9H); 1 3c NMR 8 219.6 (s), 135.6 (d), 135.6 (d), 133.4 
(s), 133.3 (s), 129.7 (d), 129.7 (d), 127.7 (d), 70.4 (t), 52.5 (s), 48.2 (t), 45.4 (t), 
42.7 (d), 36.3 (t), 34.1 (t), 26.9 (q), 24.8 (t), 19.3 (s). HRMS for C25H32O2S1 
M+H, calcd: 393.2250. Found: 393.2201. Anal. Calcd for C25H3202Si: C, 
76.48; H, 8.22. Found: C, 76.32; H, 8.30. 

8-Ethoxvc arbonvlbicyclo[3.2.1]octan-3-one (204^ . The mixture of tricyclic 
ketone 173 (112 mg, 0.571 mmol), TBTH (384 ml_, 1.43 mmol) and AIBN (30 
mg, 0.171 mmol) in benzene (5.7 ml_) was degassed with argon for 15 minutes 
and refluxed at 80°C for 5 hours. The reaction mixture was rotovaped and 
chromatographed to afford 204 (106 mg, 94%) as a colorless oil. Rf (1:2 
hexane/ether) 0.53. IR (KBr) 2956, 1709, 1642; 1 H NMR 5 4.22 (q, J=7 Hz, 2H), 
2.80 (d, J=15 Hz, 2H), 2.77 (s, 3H), 2.24 (d, J=15 Hz, 2H), 1.89 (d, J=9 Hz, 2H), 
1.73-1.55 (m, 2H), 1.30 (t, J=7 Hz, 3H); 13 C NMR 8 211.6 (s), 172.5 (s), 60.5 (t), 
49.6 (d), 46.2 (2C, t), 36.6 (2C, d), 29.1 (2C, t), 14.3 (q). Anal. Calcd for 
C1 1 H16O3: C, 67.32; H, 8.22. Found: C, 67.18; H, 8.34. 



99 



1 .2-Dimethoxycarbonvlbicvclor3.3.0]octan-3-one (206/206T) . To a solution of 
tricyclic ketone 174 (450 mg, 1.89 mmol) in benzene (20 ml_) was added TBTH 
(1380 mg, 4.74 mmol) and AIBN (100 mg, 0.61 mmol). The mixture was 
degassed with argon stream for 15 minutes and refluxed at 80°C for 3 hours. 
The reaction mixture was rotovaped and chromatographed to yield 206/206T 
(270 mg, 59%) as a clear thick oil. Rf (1/2 hexane/ether) 0.48. IR (KBr) 3427 
(broad), 1729, 1664, 1626 (weak), 1286; 1 H NMR 5 10.55 (s, 0.8H), 3.78 (s, 
3.0H), 3.70 (s, 3.0H), 2.93 (m, 1.1 H), 2.65 (m, 1.0H), 2.39 (m, 1.0 H), 2.26 (d, 
J=18 Hz, 1.1H), 1.50-2.10 (m, 7.6H), 1.40 (m, 1.0H), 1.26 (m, 0.5H), 0.90 (m, 
0.5H); 13c NMR 8 177.0 (s), 176.3 (s), 119.6 (s), 119.0 (s), 103.9 (s), 68.2 (s), 
61.7 (s), 52.1 (q), 51.2 (q), 44.4 (d), 38.9 (t), 35.6 (t), 35.2 (t), 26.0 (t), 25.1 (d), 
23.4 (d). Anal. Calcd for C12H16O5: C, 59.99; H, 6.71. Found: C, 59.87; H, 6.82. 
2.4-Dinitrophenvlhydrazone (207^ . In a dry flask, 2,4-dinitrophenylhydrazine 
(125 mg, 0.631 mmol) was dissolved in methanol (4 ml_) with concentrate 
H2SO4 (0.2 ml_), warmed by water bath. In another dry flask, bicyclic ketone 
204 (100 mg, 0.510 mmol) was dissolved in methanol (5 ml_). To this solution 
was dropwise added the dinitrophenylhydrazine solution. Orange precipitate 
formed immediately. After chilled in ice bath, the precipitate was collected by a 
Buchner funnel. This dark orange crude product was multiply recrystallized with 
ethanol-water. Clean product 207 (105 mg, 55%) was obtained as golden 
flakes. Melting point: 106-107.5°C. 1 H NMR 5 11.14 (s, 1H), 9.10 (d, J=2 Hz, 
1H), 8.28 (dd, J=10 Hz, 2 Hz, 1H), 7.95 (d, J=10 Hz, 1H), 4.22 (q, J=7 Hz, 2H), 
2.82 (d, J=15 Hz, 2H), 2.78 (s, 3H), 2.53 (m, 2H), 1.90 (m, 2H), 1.64 (m, 1H), 
1.47 (m, 1H), 1.31 (t, J=7 Hz, 3H); 13 C NMR 5 196.1 (s), 172.3 (s), 158.1 (s), 
145.1 (s), 139.6 (s), 129.8 (d), 123.4 (d), 116.3 (d), 60.4 (t), 49.8 (d), 38.3 (t), 
36.1 (d), 35.4 (d), 31.8 (t), 29.6 (t), 28.3 (t), 14.3 (q). Anal. Calcd for 
C17H20O6N4: C, 54.25; H, 5.36; N, 14.89. Found: C, 54.15; H, 5.37; N, 14.93. 



100 



8-Ethoxvcarbonyl-8-deuterobicvclo[3. 2.1]octan-3-one (204D). A mixture of 
tricyclic ketone 173 (145 mg, 0.747 mmol), tributyltin deuteride (872 mg, 2.99 
mmol) and AIBN (37 mg, 0.224 mmol) in benzene (1.5 ml_) was degassed with 
argon stream for 15 minutes and refluxed at 80°C for 3 days. The reaction 
mixture was directly chromatographed to give recovered 173 (47 mg) and the 
cyclopropane fragmentation product 204D (78 mg, 78%). Rf (1 :1 ether/hexane) 
0.68. 1 H NMR 8 4.15 (q, J=7 Hz, 2H), 2.72 (d, J=15 Hz, 2H), 2.68 (d, J=3.6 Hz, 
2H), 2.17 (d, J=15 Hz, 2H), 1.84-1.80 (m, 2H), 1.51 (m, 2H), 1.23 (t, J=7 Hz, 3H); 
13c NMR 6 211.4, 172.4, 60.4, 49.1 (very weak, triplet, J=22 Hz), 46.1, 36.5, 
28.9, 14.2. HRMS forCnHi5DC>3 M+H, calcd: 198.1240. Found: 198.1239. 
8-Ethoxvcarbonvl-8-cvanoisopropvlbicvclo[3.2.11octan-3-one (210V A mixture 
of tricyclic ketone 173 (97 mg, 0.500 mmol), TBTH (1345 ul, 5.00 mmol) and 
AIBN (410 mg, 2.50 mmol) in benzene (5 ml_) was degassed with argon stream 
for 15 minutes and refluxed at 80°C for 1 hour. The reaction mixture was 
rotovaped and directly chromatographed to afford 210 (136 mg) as a semi- 
solid. Rf (2:1 ether/hexane) 0.63. 1 H NMR 6 4.15 (q, J=7 Hz, 2H), 2.72 (d, J=15 
Hz, 2H), 2.67 (d, J=4.5 Hz, 2H), 2.16 (d, J=15 Hz, 2H), 1.84-1.80 (m, 2H), 1.65 
(s, 6H), 1.51 (m, 2H), 1.22 (t, J=7 Hz, 3H); 1 3c NMR 5 211.1 (s), 172.3 (s), 118.9 
(s), 68.0 (s), 60.3 (t), 46.0 (d), 36.4 (t), 28.9 (t), 24.9 (2C, q), 14.1 (q). 
1 .2-Dimethoxvcarbonvlbicvclor3.3.01oct-2-ene (213^ . Ketone 206/206T (220 
mg, 0.92 mmol) was dissolved in methanol (3 mL) and chilled to -78°C. To the 
solution was added sodium borohydride (140 mg, 3.67 mmol). After stirring for 3 
hours, the reduction was quenched with water and multiply extracted with ethyl 
acetate. The organic extract was rotovaped to afford 211 (200 mg, 90%) as an 
oil. Rf (ether) 0.31. Crude 211 (200 mg, 0.83 mmol) and triethylamine (417 mg, 
4.13 mmol) were dissolved in CH2CI2 (2 mL) and chilled to -20°C. To this 
mixture was dropwise added mesyl (i.e. methanesulfonyl) chloride (188 mg, 



101 



1.65 mmol, in 2 ml_ CH2CI2). After stirring for 1 hour, the reaction mixture was 
allowed to warm up to room temperature and stirred for 2 hours. The mixture 
was rotovaped to afford crude solid mesylate 21 2. To the mesylate was added 
DBU (628 mg, 4.13 mmol) and THF (3 ml_). This mixture was refluxed overnight. 
The reaction was quenched with water and extracted with ether. The ether 
extract was dried, rotovaped and chromatographed to give 213 (35 mg, 20%) 
as a clear oil. Rf (1 :1 hexane/ether) 0.45. 1 H NMR 6 6.82 (m, 1 H), 3.74 (s, 3H), 
3.65 (s, 3H), 2.83 (m, 1H), 2.24 (m, 1H), 2.12 (m, 1H), 1.94 (m, 2H), 1.75 (m, 2H), 
1.68(m, 1H), 1.38 (m, 1H); 1 3c NMR 6 176.6 (s), 164.6 (s), 144.8 (d), 137.6 (s), 
65.7 (s), 52.2 (q), 51.5 (q), 49.4 (d), 39.7 (t), 35.6 (t), 35.4 (t), 26.1 (t). Anal. Calcd 
for C12H16O4: C, 64.27; H, 7.19. Found: C, 64.12; H, 7.31. 

1 -FormvltricyclofS.S.O.O^octane-S-one (240^ . Compound 173 (1705 mg, 
8.79 mmol) was dissolved in CH2CI2 (22 ml_) at -78°C. To the solution was 
dropwise added DIBAH (1.0 M in hexane, 44 ml_, 44 mmol) through a syringe. 
After stirring at -78°C for 1 hour, the dry ice bath was removed and the reaction 
mixture was allowed to warm up to room temperature. The reaction was 
complete overnight. The reaction then was chilled to -78°C and quenched with 
ethanol. To clear up the gray glue formed, at room temperature an aqueous 
solution of Rochelle's salt was added and the mixture was stirred vigorously for 

2 hours. The mixture was multiply extracted with ethyl acetate. The ethyl acetate 
extracts were combined, dried and rotovaped to afford crude tricyclic diol 198 
(1600 mg) as a thick oil. Without further purification, crude diol 198 was 
dissolved in CH2CI2 (9 ml_). PCC (9.50 g, 44 mmol) and silica gel (9.50 g) were 
finely ground in a mortar. The powder was suspended in CH2CI2 (88 ml_). This 
suspension was added to the stirred solution of diol 198 at room temperature. 
The oxidation was complete in 2 hours. Then the dark brown suspension was 
filtered through a celite bed in a Buchner funnel and the bed was rinsed with 



102 



copious amount of ether. The organic solution was then rotovaped and the 
residue was chromatographed to afford 240 (686 mg, 52%) as a thick oil which 
slowly solidified in refrigerator. Rf (ether) 0.57. IR (KBr) 3444, 2957, 2876, 1725, 
1 702, 1310,1 255, 1 1 96, 1 1 52, 1 039; 1 H NMR 8 9.21 (s, 1 H), 3.55-3.50 (m, 1 H), 
2.79 (t, J=10 Hz, 1H), 2.75-2.62 (m, 2H), 2.30-2.12 (m, 2H), 1.90 (d, J=18 Hz, 
1H), 1.78-1.65 (m, 2H); 1 3c NMR 5 210.6 (s), 196.2 (d), 60.2 (s), 47.1 (d), 47.0 
(t), 40.7 (t), 38.5 (d), 34.9 (d), 24.4 (t). Anal. Calcd for C9H10O2: C, 71.98; H, 
6.71. Found: C, 71 .87; H, 6.77. 

1-EthQxvcarbonvltricvclo[3.3.0.Q2 ^]octan-3-one ethylene ketal (2411 A mixture 
of 173 (2000 mg, 10.3 mmol), anhydrous ethylene glycol (1.72 ml_, 30.9 mmol), 
PPTS (170 mg, catalyst) and benzene (20 mL) was refluxed overnight in a flask 
equipped with a Dean-Stark tube. After 12 hours the reaction mixture was 
poured into cold water and extracted with ether. The ether extract was dried, 
rotovaped and chromatographed to yield 241 (2203 mg, 90%) as a colorless oil 
and a small amount of unreacted 173 (148 mg) was recovered. Rf (1:1 
ether/hexane) 0.44. IR (KBr) 1 720; 1 H NMR 8 4.1 1 (q, J=7 Hz, 2H), 4.00-3.85 (m, 
4H), 3.18-3.13 (m, 1H), 2.53-2.45 (m, 1H), 2.33-1.95 (m, 5H), 1.63 (d, J=14 Hz, 
1H),1.60-1.54 (m, 1H), 1.24 (t, J=7 Hz, 3H); ™C NMR 8 173.1 (s), 117.5 (s), 64.7 
(t), 63.8 (t), 60.2 (t), 48.2 (t), 48.2 (s), 45.0 (d), 40.6 (d), 40.4 (t), 37.7 (d), 23.6 (t), 
14.1 (q). Anal. Calcd for C13H18O4: C, 65.53; H, 7.61. Found: C, 65.38; H, 7.68. 
Tricyclic diol 244. Tricyclic ethyl ester 241 (2000 mg, 8.40 mmol) was dissolved 
in CH2CI2 (16 mL) and chilled to -78°C. To this solution was dropwise added 
DIBAH (1.0 M in hexane, 33.6 mL, 33.6 mmol) through a syringe. The reaction 
was warmed up to room temperature and stirrer for 12 hours. Chilled to 0°C, the 
reaction was quenched with water. The aqueous solution of Rochelle's salt was 
added and stirred vigorously till the two-layer separation line was clear. The 
mixture was multiply extracted with ethyl acetate. The acetate extract was dried, 



103 



rotovaped and chromatographed to give diol 244 (1 176 mg, 71%) as a thick oil. 
Rf (ether) 0.15; Rf (ethyl acetate) 0.25. IR (KBr) 3356, 2937, 2860, 1104, 1068, 
1 01 8; 1 H NMR 5 4.51 (m, 1 H), 3.79-3.43 (m, 6H), 3.1 1 (s, 1 H), 2.96 (s, 1 H), 2.63 
(m, 1H), 2.51-2.40 (m, 1H), 2.30-2.20 (m, 1H), 2.12-1.99 (m, 1H), 1.96-1.86 (m, 
1H), 1.62-1.51 (m, 3H), 1.39 (d, J=14 Hz, 1H); 13 C NMR 5 83.7 (d), 70.0 (t), 65.3 
(t), 61.8 (t), 50.4 (s), 44.5 (d), 44.3 (t), 39.8 (t), 35.0 (d), 32.5 (d), 24.6 (t). HRMS 
forCnHi803 M+H, calcd: 199.1334. Found: 199.1380. 
1-Hvdroxvmethyltricvclo[3.3.0.o£ £]octan-3-one ethylene ketal (242). Ethyl 
ester 241 (3210 mg, 13.5 mmol) was dissolved in CH2CI2 (25 ml_) and chilled 
to -78°C. To this solution was dropwise added DIBAH (1.0 M in hexane, 28.3 
mL, 28.3 mmol) through a syringe. After 1 hour, the reaction was quenched with 
ethanol, and diluted with a large amount of ethyl acetate. The aqueous solution 
of Rochelle's salt was added and the mixture was vigorously stirred to clear up 
the aqueous phase. The mixture was multiply extracted with ethyl acetate. The 
organic extract was dried, rotovaped and chromatographed to give 242 (2530 
mg, 96%) as a colorless oil. Rf (ether): 0.36. IR (KBr) 3406; 1 H NMR 6 4.01-3.66 
(m, 6H), 3.34-3.30 (m, 1H), 2.71-2.67 (m, 1H), 2.18-1.88 (m, 3H), 1.59 (d, J=14 
Hz, 1H), 1.57-1.47 (m, 3H); 1 3c NMR 5 119.0 (s), 64.6 (t), 64.5 (t), 63.4 (t), 49.0 
(s), 48.5 (t), 42.7 (d), 40.0 (t), 38.6 (d), 30.0 (d), 23.9 (t). HRMS for C11H16O3 
M+H, calcd: 197.1178. Found: 197.1226. 

Oxidation of tricyclic alcohol 242 using PCC . Tricyclic alcohol 242 (280 mg, 
1.43 mmol) was dissolved in CH2CI2 (1.5 mL). PCC (618 mg, 2.86 mmol) and 
silica gel (618 mg) were finely ground in a mortar. This mixture was suspended 
in CH2CI2 (6 mL). This suspension was added to the stirred 242 solution. The 
oxidation was complete in 1.5 hour. The dark reaction mixture was diluted with 
ether and filtered through a celite bed in a Buchner funnel. The bed was rinsed 
with copious amount of ether. The ether solution was rotovaped and 



104 



chromatographed to give 1-formyltricyclo[3.3.0.0 2 ' 8 ]octane-3-one 240 (144 mg, 
67%), Rf (ether) 0.57; and 243 (10 mg, 4%), Rf (ether): 0.36. 
1-Formvltricvclo[3.3.0.0^]octan-3-one ethylene ketal (243) . Primary alcohol 

242 (2050 mg, 10.5 mmol) was dissolved in CH2CI2 (20 ml_). To this solution, 
celite (4.0 g) and PDC (7866 mg, 21.0 mmol) were added. The reaction mixture 
was stirred overnight. It was diluted with a large amount of ether and vigorously 
stirred for 20 minutes. The ether solution was decanted and a new portion of 
ether was added to the mud. This process was repeated 5 times. The ether 
solutions decanted were combined, rotovaped and chromatographed to give 

243 (1368 mg, 67%) as an oil. Rf (2:1 ether/hexane) 0.45. 1 H NMR 5 9.09 (s, 
1H), 4.03-3.85 (m, 4H), 3.25-3.20 (m, 1H), 2.50-2.23 (m, 4H), 2.13-1.99 (m, 2H), 
1.69 (d, J=15 Hz, 1H), 1.66-1.59 (m, 1H); 1 3c NMR 5 198.0 (d), 116.9 (s), 64.8 
(t), 63.9 (t), 59.6 (s), 48.3 (t), 45.3 (d), 40.5 (t), 37.9 (d), 37.6 (d), 23.3 (t). HRMS 
forCnHi403, calcd: 194.0943. Found: 194.0958. 

1 -M -Hydroxv-3-butenvntricvclo[3.3.0.o££loctan-3-one (239) . Aldehyde 243 
(480 mg, 2.47 mmol) was dissolved in THF (12 ml_) and chilled to -78°C. To the 
solution was dropwise added allylmagnesium bromide (1.0 M in ether, 9.9 ml_, 
9.9 mmol) through a syringe. After 1 hour, the dry ice bath was removed. After 
stirring for another hour, the reaction was quenched with ethanol and acidified 
by 3 M HCI. After stirring for 30 minutes, the mixture was extracted with ethyl 
acetate. The acetate phase was dried, rotovaped and chromatographed to give 
239 (403 mg, 85%) as an oil. The GC ratio of the two diastereomers of 
239 was 1.3:1. Rf (ether) 0.50. IR (KBr) 3419, 1709; 1 H NMR 5 5.93-5.78 (m, 
1H), 5.20-5.10 (m, 2H), 3.84-3.70 (m, 1H), 3.00-2.93 (m, 1H), 2.82 (s, broad, 
1H), 2.64-2.52 (m, 1H), 2.45-2.25 (m, 2H), 2.16-2.00 (m, 4H), 1.80-1.74 (1H: 
1.77, d, J=18 Hz, 0.43 H; 1.76, d, J=18 Hz, 0.57 H), 1.69-1.53 (m, 2H); 13c NMR 
5 215.5 (s), 134.5 (d), 117.8 (t), 71.2 (d), 55.2 (s), 47.3 (t), 43.2 (d), 40.2 (t), 40.0 



105 



(t), 38.3 (d), 34.3 (d), 25.1 (t) for the major diastereomer and 5 215.3 (s), 134.3 
(d), 117.9 (t), 70.9 (d), 54.8 (s), 47.1 (t), 42.7 (d), 40.0 (t), 39.8 (t), 38.2 (d), 34.6 
(d), 25.1 (t) for the minor diastereomer. HRMS for C12H16O2 M+H, calcd: 
193.1229. Found: 193.1226. 

1 1 -Hvdroxv-9-methvltricvclo[6.3.0.Ql^1undecan-3-one (245) . Compound 239 
(120 mg, 0.625 mmol) was dissolved in benzene (6.2 ml_). To the solution was 
added TBTH (336 ml_, 1.25 mmol) and AIBN (102 mg, 0.625 mmol). The mixture 
was degassed with argon for 15 minutes and refluxed overnight. After 14 hours, 
ethanol was added to quench the reaction. The mixture was rotovaped and 
chromatographed to yield cyclization product 245 (113 mg, 94%) as an oil. The 
GC ratio of the major (endo-C9-methyl) and the minor (exo-C9-methyl) 
cyclization products was 57:1. The GC ratio of the two C1 1 diastereomers of the 
endo-C9-methyl products was still 1.3:1. The major and minor cyclization 
products had same Rf and they were not separable from each other. Rf (ether) 
0.56. IR (KBr) 3432, 1 727; 1 H NMR 8 3.98-3.82 (m, 1 H), 3.02-2.90 (m, 1 H), 2.73- 
2.40 (m, 3H), 2.27-2.00 (m, 3H), 1.96-1.20 (m, 6H), 0.97-0.92 (3H: 0.96, d, J=7 
Hz; 0.93, d, J=7 Hz); ™C NMR 8 221.2 (s), 81.2 (d), 59.6 (s), 55.2 (d), 51.3 (t), 
44.0 (t), 41.8 (d), 40.2 (t), 34.0 (t), 31.0 (d), 27.9 (t), 14.5 (q) for the major C11 
diastereomer and 8 220.7 (s), 77.3 (d), 63.0 (s), 54.9 (d), 46.7 (d), 44.9 (t), 43.1 
(t), 41.9 (t), 34.0 (t), 33.2 (d), 27.0 (t), 14.6 (q) for the minor C11 diastereomer. 
HRMS forCi2Hi802 M+H, calcd: 195.1385. Found: 195.1383. 
1 1 -Oxo-9- methvltricvclo[6.3.0.0l i 5lundecan-3-one (249) . Triquinane alcohol 
245 (31 mg, 0.16 mmol) was dissolved in CH2CI2 (0.5 ml_). PCC (70 mg, 0.32 
mmol) and silica gel (70 mg) were finely ground and added to the 245 solution. 
After stirring for 1 hour, a large amount of ether was added and the dark brown 
suspension was filtered through a celite bed in a Buchner. The bed was 
thoroughly rinsed with ether. The ether phase was rotovaped and 



106 



chromatographed to give the oxidation product 249 (24 mg, 78%) as an oil. Rf 
(2:1 ether/hexane) 0.47. IR (KBr) 1728; 1 H NMR 8 2.70-2.66 (m, 1H), 2.64-2.58 
(m, 2H), 2.46-2.04 (m, 6H), 1.93-1.83 (m, 1H), 1.56-1.45 (m, 1H), 1.39-1.21 (m, 
2H), 1.14 (d, J=6 Hz, 3H); 1 8 C NMR 5 222.1 (s), 21 6.5 (s), 64.4 (s), 54.4 (d), 46.6 
(t), 45.6 (d), 43.8 (t), 43.0 (t), 34.8 (t), 30.1 (d), 26.9 (t), 16.2 (q). HRMS for 
C12H16O2, calcd: 192.1150. Found: 192.1159. 

1 .5-Dimethvlbicvclo[2.2.0]octane-3.7-dione (250) . 78 This synthetic work was 
identical to that described by Weiss and co-workers. 78 a buffer solution (pH 
8.3) was prepared with NaHC03 (5.6 g) and water (400 mL). In an Erlenmeyer 
flask, dimethyl ketomalonate 253 (24.3 g, 140 mmol) was mixed with the buffer 
solution (70 mL). To this rapidly stirred mixture, 2,3-butadione 254 (6.0 g, 70 
mmol) was added. The mixture was stirred 18 hours and a yellow suspension 
was obtained. Solid 255 was collected by a Buchner funnel and washed with 
water until the solid was white in color. HRMS for C18H22O10, calcd: 398.1213. 
Found: 398.1172. White solid 255 was then dissolved in 1 M HCI (200 mL) and 
glacial acetic acid (39 mL). The mixture was vigorously stirred and refluxed for 8 
hours. After chilled in an ice bath, the mixture was multiply extracted with 
chloroform. The chloroform extracts were combined and washed with water and 
NaHC03 (aq-) until the aqueous layer neutral in pH. The chloroform solution 
then was dried and rotovaped to afford 250 (10.2 g, 88%) as a white solid. Rf 
(ether) 0.45. 1 H NMR 8 2.41 (d, J=18 Hz, 4H), 2.34 (d, J=18 Hz, 4H), 1.23 (s, 
6H); 13 C NMR 8 215.9 (2C, s), 50.7 (4C, t), 45.2 (2C, s), 21.7 (2C, q). HRMS for 
C10H14O2, calcd: 166.0994. Found: 166.0990. Anal. Calcd for C10H14O2: C, 
72.26; H, 8.49. Found: C, 72.13; H, 8.44. 

2-Bromo-1 .5-dimethvlbi cvclor2.2.0]octane-3.7-dione (251^ .80 This synthetic 
work was identical to that described by Gleiter and co-workers. 80 A solution of 
dione 250 (2.0 g, 12.1 mmol) in chloroform (20 mL) and ethyl acetate (20 mL) 



107 



was refluxed for 30 minutes in a 3-necked flask. To the refluxed mixture, 
anhydrous CuBr2 powder (3.8 g, 16.9 mmol) was added in small portions in 
more than 4 hours. A new small portion of the dark green CuBr2 was added 
only after the previously added CuBr2 had totally turned yellow in color. After 
the completion of CuBr2 addition, the reaction mixture was refluxed overnight. A 
mixture of yellow solid and orange solution was then obtained. The yellow solid 
was removed with a Buchner funnel and the orange organic filtrate was washed 
with water and NaHC03 (aq.). The organic solution then was dried, rotovaped 
and chromatographed. The bromination product 251 (1.35g, 46%) was isolated 
as a white crystal. Rf (ether) 0.52. 1 H NMR 8 4.58 (s, 1H), 2.57-2.26 (m, 6H), 
1.42 (s, 3H), 1.32 (d, J=0.9 Hz, 3H). HRMS for CirjHi302Br, calcd: 244.0099. 
Found: 244.0029. 

1 .S-DimethvltricyclofS.S.O.O^&joctane-ST-dione (252) . 80 This synthetic work 
was identical to that described by Gleiter and co-workers.^O a solution of DBU 
(871 u.L, 5.84 mmol) in anhydrous acetonitrile (3.0 ml_) was added dropwise to 
the stirred solution of bromodiketone 251 (1300 mg, 5.31 mmol) in anhydrous 
acetonitrile (13.3 ml_). The mixture was stirred overnight at room temperature. 
The reaction mixture then was rotovaped and pumped to remove acetonitrile. 
The residue was dissolved in chloroform and was washed with water, 1M HCI, 
and NaHC03 (aq.). The orange chloroform phase was decolorized with 
charcoal and dried with MgS04. The chloroform phase then was rotovaped and 
the residue was chromatographed. The desired product 252 was isolated as a 
white crystal (628 mg, 72%). Rf (ether) 0.39. 1 H NMR 5 2.56 (d, J=17 Hz, 2H), 
2.36 (s, 2H), 2.16 (d, J=17 Hz, 2H), 1.51 (s, 3H), 1.47 (s, 3H); 1 3c NMR 5 208.3 
(2C, s), 56.2 (2C, t), 47.5 (2C, d), 41.8 (2C, s), 22.8 (q), 13.6 (q). Anal. Calcd for 
C10H14O2: C, 73.15; H, 7.37. Found: C, 72.98; H, 7.32. 



108 



Preparation of 252 using Barluenga's iodination method . 81 To the solution of 
dione 250 (1000 mg, 6.02 mmol) and white crystal HgCl2 (820 mg, 3.01 mmol) 
in CH2CI2 (12 ml_) was added iodine (1530 mg, 6.02 mmol). HgCl2 was not 
soluble in CH2CI2 and the reaction mixture turned into dark purple after the 
iodine addition. A dark orange powder (Hgl2) gradually formed and 
accumulated in amount. After stirring for 6 hours, the insoluble Hgl2 was 
removed by a Buchner filtration. The CH2CI2 solution then was washed with 0.5 
M Na2S203 and saturated Kl aqueous solutions. The organic phase was dried 
and rotovaped to give 256 (1.43 g) as a crude light brown solid. The solid was 
dissolved in acetonitrile (13 ml_). To this stirred solution was dropwise added 
DBU (880 uL, 5.90 mmol, in 3 mL acetonitrile) through an additional funnel. The 
mixture was stirred overnight and then was rotovaped. The residue was 
dissolved in CHCI3. The solution was washed by water, 1 M HCI and saturated 
NaHC03 (aq.). The organic phase then was dried, rotovaped and the residue 
was chromatographed to afford 252 (508 mg, 51%) as a white needle crystal. 
Rf (ether) 0.39. 

Preparation of 252 using Horiuchi's iodination method . 82 A dark purple mixture 
of dione 250 (3000 mg, 18.1 mmol), iodine (5.05 g, 19.9 mmol) and 
Cu(OAc)2»H20 (4.35 g, 21.7 mmol) in glacial acetic acid (450 mL) was stirred 
overnight at 60°C in a flask equipped with a condenser. A green solution with 
white precipitate Cul formed. The white precipitate was removed by simple 
filtration and the filtrate was poured into 400 mL water. The mixture was 
extracted with ether. The ether extract was washed with water and saturated 
NaHC03 (aq.) to remove acetic acid. The ether phase was rotovaped to give a 
dark red oil. It was dissolved in CHCI3 and multiply washed with water and 
saturated NaHC03 (aq.) until the aqueous layer not acidic. The CHCI3 phase 
was dried and rotovaped to afford a crude orange oil. It was dissolved in 



109 



acetonitrile (40 ml_). To this solution was added DBU (3.5 ml_, 23.3 mmol, in 12 
ml_ acetonitrile) dropwise. The reaction mixture was stirred overnight and then 
rotovaped. The residue was dissolved in CHCI3. The solution was washed with 
water, 1 M HCI and saturated NaHC03 (aq.). The organic phase was dried, 
rotovaped and chromatographed to give 252 (678 mg, 25%) as white needle 
crystal. Rf (ether) 0.39. 

7-(3-Butenyl)-1.5-dimethyl-7 -hydroxvltricvclof3.3.0.0^flloctan-3-one (238). The 
dione 252 (280 mg, 1.71 mmol) was dissolved in THF (5.7 mL) and chilled to 
-78°C. To the stirred solution was dropwise added 3-butenylmagnesium 
bromide (0.5M in THF, 4.44 mL, 2.22 mmol) through a syringe in 10 minutes. 
The reaction was quenched in 3 hours with water, acidified with 1 M HCI and 
extracted with ethyl acetate. The acetate extract was dried, rotovaped and 
chromatographed. Unreacted starting dione 252 (46 mg) was recovered and 
238 (188 mg, 64%) was isolated as a white solid. The GC ratio for the Grignard 
addition stereoselectivity was found higher than 100:1. Rf (ether) 0.55. 1 H NMR 
8 5.82 (m, 1H), 4.95 (m, 2H), 3.42 (s, 1H), 2.40-2.08 (m, 4H), 2.00-1.67 (m, 6H), 
1.24 (s, 3H), 1.21 (s, 3H); 1 3c NMR 5 214.9 (s), 138.6 (d), 114.4 (t), 80.3 (s), 
58.5 (t), 54.8 (t), 50.4 (d), 49.5 (s), 46.3 (s), 45.7 (d), 42.3 (t), 28.7 (t), 23.0 (q), 
14.8 (q). HRMS for C14H20O2 M+H, calcd: 221.1542. Found: 221.1544. Anal. 
Calcd for C14H20O2: C, 76.33; H, 9.15; Found: C, 76.31 ; H, 9.16. 
Linear triquinane 259 . Tricyclic ketone 238 (34 mg, 0.155 mmol), TBTH (125 
mL, 0.465 mmol) and AIBN (25 mg, 0.155 mg) were dissolved in benzene (0.6 
mL). The mixture was degassed with steady argon stream for 15 minutes and 
refluxed overnight. The reaction was quenched with ethanol and 
chromatographed to afford 259 (28 mg, 83%) as an oil. The GC ratio for the 
endo-C9-methyl selectivity was higher than 4:1. Rf (ether) 0.68. IR 4000 (broad), 
2956, 1708, 1462; 1H NMR 8 2.35 (q, J=18 Hz, 1H), 1.97-1.85 (m, 2H), 1.73- 



110 



1.66 (m, 2H), 1.53-1.24 (m, 9H), 0.91-0.78 (m, 6H); 1 3C NMR 5 214.1 (s), 81.0 
(s), 58.9 (s), 55.0 (t), 50.0 (d), 46.5 (s), 46.0 (d), 43.1 (t), 29.3 (t), 27.4 (t), 23.2 (q), 
15.0 (q), 13.7 (q), 8.8 (t). HRMS for C14H22O2, calcd: 222.1620. Found: 
222.1616. Anal. Calcd for C14H22O2: C, 75.63; H, 9.97; Found: C, 75.62; H, 
9.95. 

Aldol reaction product 263E/T . A mixture of cyclopropyl ketone 137 (200 mg, 
1.14 mmol), TBTH (458 u.L, 1.71 mmol) and AIBN (56 mg, 0.34 mmol) in 
benzene (5 ml_) was degassed with argon for 15 minutes. The mixture was 
refluxed for 2 hours and cooled to room temperature. Benzaldehyde 262 (346 
uL, 3.41 mmol) then was added. The mixture was stirred overnight. The mixture 
then was rotovaped and chromatographed to give diastereomic mixture 
263E/T (312 mg, 97%) as a thick oil. The ratio of erythro 263E to threo 263T 
was 4.4:1 by proton NMR integration. Rf (1:1 ether/hexane) 0.24. For erythro 
263E, 1H NMR 5 7.89 (d, J=9 Hz, 2H), 7.44-7.17 (m, 5H), 6.90 (d, J=9 Hz, 2H), 
5.05 (d, J=4.5 Hz, 1H), 3.84 (s, 3H), 3.67 (m, 1H), 2.58 (s, 1H), 1.43-1.31 (m, 
2H), 0.76 (t, J=7 Hz, 3H); ™C NMR 5 203.7, 163.8, 142.1, 130.6 (2C), 130.0, 
128.1 (2C), 127.2, 126.1 (2C), 113.8 (2C), 73.8, 55.4, 53.5, 20.4, 12.1. For threo 
263T, 1H NMR 8 4.99 for the carbinol proton (d, J=5.9 Hz); 1 3C NMR 5 75.6 for 
the carbinol. HRMS forCi8H20O3 M+H, calcd: 285.1491. Found: 285.1463. 
Aldol reaction product 265 . A mixture of cyclopropyl ketone 137 (200 mg, 1.14 
mmol), TBTH (458 uL, 1.71 mmol) and AIBN (56 mg, 0.34 mmol) in benzene (4 
ml_) was degassed with argon for 15 minutes. The mixture was refluxed for 2 
hours and cooled to room temperature. Cyclohexanecarboxaldehyde 264 (412 
IllL, 3.41 mmol) then was added. The mixture was stirred for 18 hours. The 
mixture then was rotovaped and chromatographed to give diastereomic mixture 
265 (303 mg, 92%) as a thick oil. The ratio of the major diastereomer to the 
minor ones was 46:1 by GC. Rf (1:1 ether/hexane) 0.36. For the major 



111 



diastereomer, 1 H NMR 6 7.96 (d, J=9 Hz, 2H), 6.96 (d, J=9 Hz, 2H), 3.87 (s, 3H), 
3.65-3.55 (m, 2H), 2.02-1.87 (m, 2H), 1.82-1.66 (m, 4H), 1.53-0.84 (m, 11H); 
13c NMR 5 204.1 (s), 163.7 (s), 130.6 (d, 2C), 130.3 (s), 113.8 (d, 2C), 76.0 (d), 
55.3 (d), 48.0 (d), 40.6 (d), 29.4 (t), 28.8 (t), 26.2 (t), 26.0 (t), 25.8 (t), 19.7 (t), 12.3 
(q). HRMS for C18H26O3, calcd: 290.1882. Found: 290.1814. 
Alkvlation reaction product 267 . A mixture of ketone 137 (200 mg, 1.14 mmol), 
TBTH (458 ul, 1.71 mmol) and AIBN (56 mg, 0.34 mmol) in benzene (4 mL) 
was degassed with argon for 15 minutes. The mixture was refluxed for 2 hours 
and cooled to room temperature. HMPA (987 u.L, 5.68 mmol) was added and 
the mixture was stirred for 5 minutes. Allyl bromide (393 4.54 mmol) was 
added and the mixture was refluxed for 24 hours. A DBU workup procedure was 
used to remove excess TBTH and other tin byproducts. 34d, 93 The reaction 
mixture was diluted with ether. Following addition of DBU (305 u.L, 2.04 mmol) 
and 2-3 drops of water, an ethereal solution of iodine was added dropwise until 
the iodine orange color persisted. Rapid suction filtration through silica gel bed 
was performed. The silica gel bed was rinsed with ether, and the solution was 
concentrated and subjected to flash column chromatography to afford 267 (212 
mg, 86%) as a thick oil. Rf (1 :1 ether/hexane) 0.72. 1 H NMR 5 7.95 (d, J=9 Hz, 
2H), 6.94 (d, J=7 Hz, 2H), 5.75 (m, 1H), 5.05-4.94 (m, 2H), 3.86 (s, 3H), 3.41 (m, 
1H), 2.38 (m, 2H), 1.69 (m, 2H), 0.87 (t, J=7 Hz, 3H); 13c NMR 8 202.0, 163.3, 
136.0, 130.4 (3C), 116.3, 113.7 (2C), 55.3, 46.8, 36.0, 25.0, 11.6. HRMS for 
C14H18O2, calcd: 218.1307. Found: 218.1304. Anal. Calcd for C14H18O2: C, 
77.03; H, 8.31; Found: C, 76.92; H, 8.37. 

Alkvlation reaction product 268 . A mixture of ketone 137 (200 mg, 1.14 mmol), 
TBTH (458 ul, 1.71 mmol) and AIBN (56 mg, 0.34 mmol) in benzene (2 mL) 
was degassed with argon for 15 minutes. The mixture was refluxed for 2 hours 
and cooled to room temperature. HMPA (987 u.L, 5.68 mmol) was added and 



112 



the mixture was stirred for 3 minutes. 1-lododecane (969 u.L, 4.54 mmol) was 
added and the mixture was refluxed for 18 hours. The mixture was directly 
subjected on flash column chromatography to give 268 (342 mg, 95%) as a 
thick oil. Rf (1 :1 ether/hexane) 0.87. 1 H NMR 5 7.87 (d, J=9 Hz, 2H), 6.84 (d, J=9 
Hz, 2H), 3.75 (s, 3H), 3.22 (m, 1H), 1.66 (m, 2H), 1.52-1.35 (m, 2H), 1.13 (m, 
16H), 0.79-0.74 (m, 6H); 13q NMR 5 202.9, 163.2, 130.8, 130.3 (2C), 113.5 
(2C), 55.2, 47.1, 32.1, 31.8, 29.8, 29.5 (2C), 29.4, 29.2, 27.5, 25.5, 22.6, 14.0, 
1 1 .8. HRMS for C21 H34O2, calcd: 31 8.2559. Found: 31 8.2554. 
1 -(4-Methoxvphenvnhept-6-enone (286) . A mixture of ketone 137 (200 mg, 
1.14 mmol), allyltributyltin (1760 ul, 5.68 mmol) and AIBN (186 mg, 1.14 mmol) 
in benzene (0.5 ml_) was degassed with argon for 10 minutes and heated at 
80°C for 1 day. Then AIBN (186 mg, 1.14 mmol) was added and the mixture 
was degassed at room temperature for 10 minutes. The mixture was again 
heated at 80°C for 1 day. The mixture was directly subjected to column 
chromatography to give unreacted 137 (105 mg) and 286 (59 mg, 24%; 50% if 
corrected with recovered 137). Rf (1:3 ether/hexane) 0.47. 1 H NMR 8 7.94 (d, 
J=9 Hz, 2H), 6.93 (d, J=9 Hz, 2H), 5.82 (m, 1H), 5.05-4.94 (m, 2H), 3.87 (s, 3H), 
2.91 (q, J=7.5 Hz, 2H), 2.10 (q, J=7 Hz, 2H), 1.75 (m, 2H), 1.48 (m, 2H); 1 3c 
NMR 5 198.9, 163.3, 138.5, 130.3 (2C), 130.1, 114.5, 113.6 (2C), 55.4, 38.0, 
33.6, 28.6, 24.0. HRMS forCi4Hi802, calcd: 218.1307. Found: 218.1304. 
8-Allvl-8-ethoxvcarbonvlbicvclof3.2.1]octan-3-one (287) . A mixture of tricyclic 
ketone 171 (330 mg, 1.70 mmol), allyltributyltin (1318 u.L, 4.25 mmol) and AIBN 
(139 mg, 0.851 mmol) in benzene (1.7 mL) was degassed with argon for 15 
minutes and refluxed for 16 hours. The mixture was directly chromatographed to 
give the allylation product 287 (376 mg, 94%) as a clear oil. Rf (1:1 
ether/hexane) 0.58. IR (KBr) 1720; 1 H NMR 8 5.70-5.57 (m, 1H), 4.99-4.97 (m, 
1H), 4.97-4.91 (m, 1H), 4.09 (q, J=7 Hz, 2H), 2.65 (d, J=15 Hz, 2H), 2.37 (dd, 



113 



J=4.2 Hz, 2.7 Hz, 2H), 2.25 (d, J=7 Hz, 2H), 2.13 (m, 2H), 1.91-1.87 (m, 2H), 
1.44 (m, 2H), 1.17 (t, J=7 Hz, 3H); 1 3C NMR 5 212.0 (s), 173.8 (s), 133.0 (d), 
118.0 (t), 60.4 (t), 58.5 (s), 47.6 (t, 2C), 39.3 (d, 2C), 27.2 (t, 3C), 14.3 (q). HRMS 
forCi4H20O3 M+H, calcd: 237.1491. Found: 237.1498. 



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BIOGRAPHICAL SKETCH 



Zhaozhong Jon Jia was born in Kaifeng, Henan, China on October 22, 
1968. As a quiet boy, he spent his early years reading books, learning painting, 
and playing with his cats and chickens. At high school he fell in love with 
chemistry under the strong influence of a great chemistry teacher Mr. Shugeng 
Luo. In September 1985, he left his hometown for Tianjin, a northern city 600 
miles away, to study chemistry at Nankai University. 

At college, organic chemistry was his obvious favorite. He dreamed that 
someday he could earn a Ph.D. degree in this field and devote his life to 
synthesizing valuable organic compounds. In his junior year, the department 
assigned him into the inorganic division and blocked his opportunity for further 
organic chemistry studies. In his final semester at Nankai, he entered Professor 
Daizheng Liao's lab to prepare and study Cu(ll)-Fe(lll) binuclear coordination 
compounds for his senior research. There for the first time he experienced real 
synthesis. In July 1989, he received his BS degree in inorganic chemistry. 

Attracted by its numerous high technology research programs and 
beautiful suburban location, he accepted a job offer from China Institute of 
Atomic Energy in Beijing. His job was to study the liquid sodium purification 
technology to support his country's sodium-cooled fast breeder nuclear reactor 
program. He and his colleagues accomplished establishment of a new sodium 
purification loop and production of "nuclear-grade pure" sodium in 1991. They 
shared an research award from China's Nuclear Industries Ministry for the work. 



121 



122 



To pursue a Ph.D. degree, he arrived at the University of Florida in 
August 1992. Eager to come back to organic chemistry, he joined Professor Eric 
Enholm's group in the October. His research efforts focused on the synthetic 
applications of ketyl radicals, generated by the reaction of a carbonyl 
functionality with tributyltin hydride or samarium diiodide. After his hard-working 
struggles in the initial one-and-a-half year with a couple of fruitless projects, he 
gradually grew up and realized that real chemistry is much more challenging 
than a written reaction or synthetic route on paper. With progress in this 
cyclopropane fragmentation project, he became a Ph.D. candidate in January 
1995, and presented his research in the national ACS meeting in March 1996 
in New Orleans. In December 1996, he obtained his Ph.D. degree in organic 
chemistry at the University of Florida in Gainesville, Florida. 

In January 1997, he joined Professor Bert Fraser-Reid's group as a 
postdoctoral research associate at the Natural Products and Glycotechnology 
Research Institute in Durham, North Carolina. 



I certify that I have read this study and that in my opinion it conforms to 
acceptable standards of scholarly presentation and is fully adequate, in scope 
and quality, as a dissertation for the degree of Doctor of Philosophy. 



Eric J. Enholm, Chairman 
Associate Professor of Chemistry 

I certify that I have read this study and that in my opinion it conforms to 
acceptable standards of scholarly presentation and is fully adequate, in scope 
and quality, as a dissertation for the degree of Doctor of Philosophy. 



Merle A. Battiste 
Professor of Chemistry 

I certify that I have read this study and that in my opinion it conforms to 
acceptable standards of scholarly presentation and is fully adequate, in scope 
and quality, as a dissertation for the degree of Doctor of Philosophy. 



William R. Dolbier, Jr. 
Professor of Chemistry 

I certify that I have read this study and that in my opinion it conforms to 
acceptable standards of scholarly presentation and is fully adequate, in scope 
and quality, as a dissertation for the degree of Doctor of Philosophy. 

Barnes M. Boncella 
Associate Professor of Chemistry 

I certify that I have read this study and that in my opinion it conforms to 
acceptable standards of scholarly presentation and is fully adequate, in scope 
and quality, as a dissertation for the degree of Doctor of Philosophy. 




MargarejO. James 
Professor of Medicinal Chemistry 



This dissertation was submitted to the Graduate Faculty of the Depart- 
ment of Chemistry in the College of Liberal Arts and Sciences and to the 
Graduate School and was accepted as partial fulfillment of the requirements for 
the degree of Doctor of Philosophy. 



December, 1996 



Dean, Graduate School